Cephem compounds, their production and use

ABSTRACT

Cephem compounds, pharmaceutically acceptable salts thereof, and methods of using same, wherein the compound has a bicyclic nitrogen-containing aromatic heterocyclic ring as the quaternary ammoniomethyl group at the 3-position and one or both of a terminal amidine residue (substituted or unsubstituted) attached to an aryl or a 5- or 6-membered heteroaryl group (substituted or unsubstituted) which is further attached through a spacer to the free N-atom of the quaternary nitrogen-containing bicyclic ring at the 3-side chain, or a terminal guanidine residue attached to an aryl or a 5- or 6-membered heteroaryl group (substituted or unsubstituted) which is further attached through a spacer to the free N-atom of the quaternary nitrogen-containing bicyclic ring at the 3-side chain.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application is a Reissue of U.S. application Ser. No. 15/369,181,filed Dec. 5, 2016, now U.S. Pat. No. 9,751,894, which claims priorityto U.S. Provisional Patent Application No. 62/265,625, filed Dec. 10,2015, entitled “Cephem Derivatives As Broad-Spectrum AntibacterialAgents”, both of which is are hereby incorporated by reference in itstheir entirety.

TECHNICAL FIELD

New cephem compounds, their pharmaceutically acceptable salts, theiruse, and the methods for preparation of these new compounds areprovided. More particularly, cephem compounds having improvedantibacterial activity, and combinations of the present cephemantibiotics with β-lactamase inhibitors that are active against a numberof resistant pathogenic microorganisms are provided.

BACKGROUND

Cephem antibiotics have been widely used for the treatment of bacterialinfections both in hospitals and in the general public. As such, it ishighly desirable to use cephem antibiotics showing activity against bothgram-positive and gram-negative bacteria. Unfortunately, due to theexistence of multiple-drug resistant gram-negative and gram-positiveorganisms, many bacteria have become highly resistant to a number ofβ-lactam drugs, including the bacteria that constitute the ESKAPEorganisms, generally encompassed by the following six pathogens:Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumonia,Acinetobacter baumanii, Pseudomonas aeruginosa and Enterobacter species.This includes a resistance to known cephems whereby the bacteria areproducing β-lactamases, including Class A (ESBL) and Class D (serineβ-lactamases) types, which have an extended substrate spectrum. As aresult, the morbidity and mortality caused by bacterial infections inboth hospital and community settings continues to rise, and has become asignificant public health concern.

There is a demand for development of new cephem compounds which exhibitmore potent antimicrobial activity in particular more effective againsta variety of β-lactamase producing gram-positive and gram-negativebacteria.

A variety of cephem compounds having a quaternary ammonium group at the3-side chain and 2-(2-aminothiazol-4-yl)-2-hydroxy-(or substitutedhydroxyl)aminoacetamido group at 7-position have been published such as,for example, U.S. Pat. Nos. 4,864,022, 5,173,485 ,5,215,982, 5,071,979,4,406,899, 4,910,301, 4,748,171, 5,010,188, International PatentApplication Nos. PCT/JP2003/013684, PCT/JP2007/056136,PCT/IB2013/002423, European Patent Application No. 2 703 406, EuropeanPatent Application No. 2 557 082; European Patent No. 2 341 053;European Patent Application No. 2 70606, United States PatentApplication No. 2013/0079319 (Shionogi), United States PatentApplication No. 2012/0264727, and European Patent Application No.2706062.

The above mentioned patents and patent applications disclose cephemcompounds whose quaternary ammoniomethyl group at the 3-position has amonocyclic or bicyclic nitrogen-containing heterocyclic or aromaticheterocyclic ring which is optionally substituted with an organic groupother than benzamidine, heteroaryl amidine, arylguanidine and heteroarylguanidine as the terminal residues.

There remains a need for new cephem compounds having increasedantibiotic efficacy, particularly in highly resistant gram-positive andgram-negative bacteria, the compounds having structural features aresignificantly different from the compounds described in the patentreferences cited above

SUMMARY

According to embodiments herein, cephem compounds and pharmaceuticallyacceptable salts thereof are provided having a bicyclic nitrogencontaining aromatic heterocyclic ring as the quaternary ammoniomethylgroup at the 3-position and the free N-atom of the said bicyclicaromatic heterocyclic ring further attached through one or two carbonspacers to a residue like benzamidine, heteroarylamidine, arylguanidineand heteroaryl guanidine or similar basic functionality bearing terminalresidues. The present compounds, and pharmaceutically acceptable saltsthereof, comprise different structural characteristics to known cephemcompounds, providing improved antibacterial activity, particularly whenused in combination with one or more β-lactamase inhibitors. It may bean advantage of the present compounds, and pharmaceutically acceptablesalts thereof, to provide antibacterial activity against“third-generation” and “fourth-generation” cephalosporin-resistantbacteria including gram-negative and gram-positive strains.

In some embodiments, the present cephem compounds, and pharmaceuticallyacceptable salts thereof, may comprise the following structuralfeatures:

(1) A bicyclic nitrogen containing aromatic heterocyclic ring as thequaternary ammoniomethyl group at the 3-position, and

(2) A terminal amidine residue (substituted or unsubstituted) attachedto an aryl or a 5- or 6-membered heteroaryl group (substituted orunsubstituted) which is further attached through a spacer to the freeN-atom of the quaternary nitrogen containing bicyclic aromaticheterocyclic ring at the 3-side chain, or

(3) A terminal guanidine residue attached to an aryl or a 5- or6-membered heteroaryl group (substituted or unsubstituted) which isfurther attached through a spacer to the free N-atom of the quaternarynitrogen containing bicyclic aromatic heterocyclic ring at the 3-sidechain.

In some embodiments, the present cephem compound may be represented bythe general formula (I) or a pharmaceutically acceptable salt thereof:

Accordingly, in some embodiments, cephem compounds and pharmaceuticallyacceptable salts thereof, i.e., compounds of formula (I) andpharmaceutically acceptable salts thereof are provided. In some aspects,these compounds may exhibit activity against pathogenic microorganisms,therefore useful in the treatment of bacterial infections in humans oranimals either alone or in combination with other β-lactam and/or nonβ-lactam β-lactamase inhibitors.

In other embodiments, pharmaceutical compositions comprising one or morecompounds of formula (I), or pharmaceutically acceptable salts thereof,and a pharmaceutically acceptable carrier or diluent are provided. Insome aspects, these compositions may exhibit activity against pathogenicorganisms.

In other embodiments, processes for the preparation of the new cephemcompounds and salts thereof, i.e., the compounds of formula (I) andpharmaceutically acceptable salts thereof are provided.

In other embodiments, pharmaceutical compositions comprising (i) one ormore compounds of formula (I), or pharmaceutically acceptable saltsthereof, (ii) one or more β-lactamase inhibitors, and (iii) apharmaceutically acceptable carrier or diluent are provided. In someaspects, these compounds may exhibit activity against pathogenicmicroorganisms.

In other embodiments, methods for treating bacterial infections in asubject, comprising providing or administering to a subject in needthereof:

-   -   (i) a therapeutically effective amount of one or more compounds        of formula (I), or pharmaceutically acceptable salts thereof;    -   (ii) a therapeutically effective amount of a pharmaceutical        composition comprising one or more compounds of formula (I), or        pharmaceutically acceptable salts thereof, and a        pharmaceutically acceptable carrier or diluent;    -   (iii) a therapeutically effective amount of a combination        comprising (a) one or more compounds of formula (I), or        pharmaceutically acceptable salts thereof, and (b) one or more        β-lactamase inhibitors; or    -   (iv) a therapeutically effective amount of a pharmaceutical        composition comprising (a) one or more compounds of formula (I),        or pharmaceutically acceptable salts thereof, (b) one or more        β-lactamase inhibitors, and (c) a pharmaceutically acceptable        carrier or diluent.

In other embodiments, the use of a compound comprising formula (I) forbacterial infections in a subject is provided. In some aspects, thecompound may further comprise a β-lactamase inihibitor, and may involvethe preparation of a therapeutically effective medicament.

According to embodiments herein, the present subject may be a humanbeing or an animal, or any other organism in which the present compoundsand compositions may provide a beneficial antibacterial effect.

DETAILED DESCRIPTION OF THE EMBODIMENTS

According to embodiments herein, cephem compounds of general formula (I)and pharmaceutically acceptable salts of the compounds of formula (I)are provided, wherein the compounds comprise antibiotics suitable foruse either alone or in combination with 3-lactamase inhibitors for thetreatment of bacterial infections. The term “antibiotic” refers to acompound or composition which decreases the viability of amicroorganism, or which inhibits the growth or proliferation of amicroorganism and is further intended to include an antimicrobial,bacteriostatic or bactericidal agent.

More specifically, the present cephem compounds, and pharmaceuticallyacceptable salts thereof, may be represented by the following generalformula (I):

In the formula (I), A is defined by the formula (Ia):

20

where X is N, C(H), C(F) or C(Cl);

B is defined as hydrogen, methyl, ethyl or represented by the formula(Ib)

wherein, R¹ and R² is independently hydrogen or lower alkyl, or R¹ andR² together may form a 3 to 6-membered spiro ring system; andm is 0 or 1.

C is defined as a quaternized bicyclic nitrogen containing aromaticheterocyclic ring.

Further, regarding object (1a), it is understood that said objectsinclude syn isomer (Z form), anti isomer (E form) and a mixture thereof.

In some preferred embodiments, the quaternized bicyclic nitrogencontaining aromatic heterocyclic rings representing C, may comprise(Ic-Iz):

where D is represented by CH₂, CH₂CH₂ or CH₂CO; and

E signifies an optionally substituted benzene ring or an optionallysubstituted 5- or 6-membered aromatic heterocyclic ring having at leastone heteroatom selected from O, S and N. Such heteroaromatic ringsinclude pyrrolyl, imidazolyl, pyrazolyl, pyridazinyl, pyrimidinyl,pyrazinyl, triazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl,thiazolyl, thiadiazolyl, furyl, thienyl and the like.

In the above formula (I), E may even more preferably selected from arylor 5- and 6-membered aromatic heterocyclic rings as indicated below:

In the above definition, optional substituents include chloro, fluoro,cyano, hydroxy, carboxy, acetyl, methoxy, ethoxy, trifluoromethyl,pyrrolidinyloxy, piperidinyloxy and the like.

Preferably, the substituent is selected from chloro, fluoro, hydroxy,methoxy, trifluoromethyl, pyrrolidinyloxy.

Having further regard to the formula (I), in the definition of E thearyl or aromatic heterocyclic ring can accommodate up to 3 substituentsselected from: F, Cl, CH₃, C₂H₅, CF₃, NH₂, NHCH₃, CONH₂, CONHCH₃, OCH₃.

In the formula (I), F is optionally substituted amidine or optionallysubstituted guanidine, and

-   -   G is hydrogen, methyl, ethyl, C₃₋₆ alkyl, C₃₋₆ cycloalkyl or an        optionally substituted 5- or 6-membered aliphatic or an        optionally substituted 5- or 6-membered aromatic heterocyclic        ring, in which the heterocyclic ring is substituted with at        least 1-2 hetero atoms selected from N, O, and S (α or β).

In the formula (I), some preferred examples of “-C-D-E-F” include thefragments (1 to 277) as shown below:

Regarding the compounds of general formula (I), it is to be understoodthat said compounds include syn-isomer, anti-isomer and a mixturethereof All tautomeric isomers are contemplated, however, for thepurposes of example, the object compound (I). As used herein the term‘isomers’ refers to different compounds that have the same molecularformula but differ in arrangement and configuration of the atoms, suchas geometrical isomers and optical isomers. For a given compound herein,it is to be understood that a substituent may be attached at a chiralcenter of a carbon atom. Therefore, enantiomers, diastereoisomers orracemates of the compound are contemplated.

It is further understood that isotopically labeled compounds, which areidentical to those recited in Formula (I), so but for the fact one ormore atoms are replaced by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number predominantly found innature are also contemplated. Examples of isotopes that can beincorporated into the present compounds may include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as, but not limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P,³⁵S and ¹⁸F respectively. The present compounds, prodrugs thereof, andpharmaceutically acceptable salts of said compounds which contain theabove mentioned isotopes and and/or other isotopes of other atoms arecontemplated. Isotopically labeled compounds and prodrugs thereof cangenerally be prepared by carrying out the procedures disclosed in theSchemes and/or in the examples below, by substituting a readilyavailable isotopically labeled reagent.

The term “β-lactamase inhibitor” refers to a compound which is capableof inhibiting β-lactamase activity, where inhibiting β-lactamaseactivity means inhibiting the activity of a class A, C or D β-lactamase.The term “β-lactamase” denotes an enzyme capable of inactivating aβ-lactam antibiotic like a cephem antibiotic. The β-lactamase inhibitormay be, but is not limited to, the following groups:

Group 1: An oxapenam derivative of the general formula (II):

in which R³ signifies OR⁴, S(O)_(n)R⁴ or a 5-6 membered heteroaromaticring which may be substituted with 1 to 5 substituents selected fromalkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halogen;whereby n=0, 1, or 2 and R⁴ is hydrogen, alkyl, (C₂-C₇)alkene,(C₂-C₇)alkyne or a 5-6 membered heteroaromatic ring which may besubstituted with 1 to 5 substituents selected from alkyl, hydroxyl,alkoxy, amino, alkylamino, dialkylamino and halogen, or apharmaceutically acceptable salt thereof.

Example of a specific compound from Group 1 is clavulanic acid (IIa):

Group 2: A penam sulfone derivative of the general formula (III):

In which R⁵ signifies hydrogen or halogen; R⁶ signifies CH₂R⁷; CH═CHR⁷wherein R⁷ is hydrogen, halogen, cyano, carboxylic acid, acyl such asacetyl, carboxamide which may be substituted, alkoxycarbonyl or a 5-6membered heteroaromatic ring which is optionally substituted with 1 to 5substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino,dialkylamino and halogen; or which is optionally fused with a 5-6membered heteroaromatic ring; CH═NR⁸ where R⁸ is amino, alkylamino,dialkylamino, aminocarbonyl, acylamino such as acetylamino, hydroxyl,alkoxy, or a pharmaceutical acceptable salt thereof. Examples of twospecific compounds from Group 2 are sulbactam (IIIa) and tazobactam(IIIb):

Group 3: A penem derivative of the general formula (IV):

In which R⁹ signifies a 5-6 membered heteroaromatic ring which may besubstituted with 1 to 5 substituents selected from alkyl, hydroxyl,alkoxy, amino, alkylamino, dialkylamino and halogen; or which isoptionally fused with a 5-6 membered heteroaromatic ring; or apharmaceutical acceptable salt thereof. Example of a specific compoundfrom Group 3 is BRL-42,715 (IVa):

Group 4: A cyclic boronic acid derivative of the general formula (V):

Wherein, R¹⁰ signifies a substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, substituted or unsubstituted carbocyclyland substituted or unsubstituted heterocyclyl. The substituent isselected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylaminoand halogen; or a pharmaceutical acceptable salt thereof. Example of aspecific compound from Group 4 is RPX-7009 (Va):

Group 5: A cyclic boronic acid of the general formula (VI):

Wherein R¹¹ signifies alkoxy, substituted or unsubstitutedthioheteroaryl or substituted carboxamide; or a pharmaceuticallyacceptable salt thereof. Examples of specific compounds from Group 5 areRPX 7262 (VIa), RPX 7282 (VIb), RPX 7381 (VIc), and RPX 7400 (VId):

Group 6: A diazabicyclooctane derivative of the general formula (VII):

Wherein, R¹² signifies carboxylic acid, alkoxycarbonyl, heteroaryl,nitrile, or carboxamide which may be substituted; or a pharmaceuticalacceptable salt thereof. Examples of several specific compounds fromGroup 6 are (VIIa-VIIg):

It has been found that the efficacy of cephem compounds of the formula(I) herein against gram-negative bacteria can be potentiated by co-usinga β-lactamase inhibitor selected from any one of the formula (II) to(VII).

A “pharmaceutically acceptable salt” of formula (I) refers to a saltwhich possesses the desired pharmacological activity of the parentcompound. Examples of the groups for forming a pharmaceuticallyacceptable salt include: inorganic base salts, ammonium salts, organicbase salts, basic amino acid salts, inorganic acid addition salts, andorganic acid addition salts. Inorganic bases that can form the inorganicbase salts include alkali metals (e.g., sodium, potassium, and lithium)and alkaline earth metals (e.g., calcium and magnesium). Organic basesthat can form the organic base salts include n-propylamine,n-butylamine, cyclohexylamine, benzylamine, octylamine, ethanolamine,diethanolamine, diethylamine, triethylamine, dicyclohexylamine,procaine, choline, picoline, N,N-dibenzylethylenediamine,N-methylglucamine, morpholine, pyrrolidine, pyridine, piperidine,N-ethylpiperidine and N-methylmorpholine. Basic amino acids that canform the basic amino acid salts include lysine, arginine, ornithine andhistidine. As will be appreciated by one skilled in the art, thecompounds of formula (I) containing a basic nitrogen atom are capable offorming acid addition salts. Such salts with pharmaceutically acceptableacids are included herein. Examples of such acids are hydrochloric,hydrobromic, phosphoric, sulfuric, citric, oxalic, maleic, fumaric,glycolic, mandelic, tartaric, aspartic, succinic, malic, formic, acetic,trifluoroacetic, methanesulfonic, ethanesulfonic,trifluoromethanesulfonic, benzenesulfonic, p-toluenesulfonic and thelike.

Moreover, some compounds of formula (I) when they contain a basic groupsuch as NH, NH₂ or pyridine and the like may form an inner zwitterionicsalt with COOH group. Such inner salts are also contemplated herein.

Pharmaceutically acceptable solvates of the compounds of formula (I) arecontemplated herein. ‘Pharmaceutically acceptable solvate’ refers to amolecular complex of a compound with one or more solvent molecules in astoichiometric or non-stoichiometric amount. Such solvent molecules arethose commonly used in the pharmaceutical art, which are known to beinnocuous to recipient, e.g., water, ethanol, and the like. A molecularcomplex of a compound or moiety of a compound and a solvent can bestabilized by non-covalent intra-molecular forces such as, for example,electrostatic forces, Van der Waals forces or hydrogen bonds. The termhydrate refers to a complex where the one or more solvent molecules arewater.

A combination of one or more of the compounds of formula (I) and one ormore β-lactamase inhibitors are provided, where the β-lactamaseinhibitors may be selected from formula (II) to (VII). Such combinationsmay exhibit a synergistic effect when used in the treatment of bacterialinfections.

A combination of pharmaceutical compositions comprising one or morecompounds of formula (I), or pharmaceutically acceptable salts thereof,and one or more pharmaceutically acceptable carriers or diluents areprovided. Further, pharmaceutical compositions comprising (i) one ormore compounds of formula (I), or pharmaceutically acceptable saltsthereof, (ii) one or more β-lactamase inhibitors, and (iii) one or morepharmaceutically acceptable carriers or diluents are also provided.Preferably, the β-lactamase inhibitors may be selected from formula (II)to (VII). It is understood that any of the compositions and combinationsherein may be administered to a subject such as, for example, byparenteral, in particular intramuscular route, oral, sublingual, rectal,aerosol or by local route in a topical application on the skin and themucous membranes. Suitable pharmaceutically acceptable carriers anddiluents include excipients such as starch, glucose, lactose, sucrose,gelatin, gum Arabic, malt, rice, flour, chalk, silica gel, sodiumstearate, glycerol monostearate, talc, sodium chloride, dried skim milk,glycerol, propylene glycol, water, ethanol, and the like. Compositionsof the present disclosure, if desired, can also contain minor amounts ofwetting, dispersing or emulsifying agents, or pH buffering agents, andpreservatives. In addition, auxiliary, stabilizing, thickening,lubricating, and coloring agents can be included. Pharmaceuticalcompositions can be formulated in a conventional manner. Properformulation is dependent upon the route of administration chosen. Thepresent pharmaceutical compositions can take the form of injectablepreparations, suspensions, emulsions, sugar-coated tablets, pellets,gelatin-capsules, capsules containing liquids, powders, granules,sustained-release formulations, suppositories, aerosols, sprays,ointments, creams or any other form suitable for use.

In a pharmaceutical composition containing the present compounds, theweight ratio of active ingredient to carrier will normally be in therange of 1:20 to 20:1.

As above, methods for treating bacterial infections in a subject arealso provided, said methods comprising administering to a subject inneed thereof:

-   -   (i) a therapeutically effective amount of one or more compounds        formula (I), or pharmaceutically acceptable salts thereof;    -   (ii) a therapeutically effective amount of a pharmaceutical        composition comprising one or more compounds of formula (I), or        pharmaceutically acceptable salts thereof, and a        pharmaceutically acceptable carrier or diluent;    -   (iii) a therapeutically effective amount of a combination        comprising (a) one or more compounds of formula (I), or        pharmaceutically acceptable salts thereof, and (b) one or more        β-lactamase inhibitors; or    -   (iv) a therapeutically effective amount of a pharmaceutical        composition comprising (a) one or more compounds of formula (I),        or pharmaceutically acceptable salts thereof, (b) one or more        β-lactamase inhibitors, and (c) a pharmaceutically acceptable        carrier or diluent.

In some embodiments, the present methods for preventing bacterialinfections in a subject comprise providing a subject in need thereof:

-   -   (i) a therapeutically effective amount of one or more compounds        formula (I), or pharmaceutically acceptable salts thereof;    -   (ii) a therapeutically effective amount of a pharmaceutical        composition comprising one or more compounds of formula (I), or        pharmaceutically acceptable salts thereof, and a        pharmaceutically acceptable carrier or diluent;    -   (iii) a therapeutically effective amount of a combination        comprising (a) one or more compounds of formula (I), or        pharmaceutically acceptable salts thereof, and (b) one or more        β-lactamase inhibitors; or    -   (iv) a therapeutically effective amount of a pharmaceutical        composition comprising (a) one or more compounds of formula (I),        or pharmaceutically acceptable salts thereof, (b) one or more        β-lactamase inhibitors, and (c) a pharmaceutically acceptable        carrier or diluent.

The present methods for treating or preventing a bacterial infection ina subject may comprise administering to a subject in need thereof (i) atherapeutically effective amount of one or more compounds formula (I),or pharmaceutically acceptable salts thereof, and (ii) a therapeuticallyeffective amount of one or more β-lactamase inhibitors. It will thus beapparent that in the treating or preventing of bacterial infections,compounds of formula (I) and β-lactamase inhibitors may be administeredto the subject in the same pharmaceutical formulation (e.g., apharmaceutical composition comprising compounds of formula (I),β-lactamase inhibitors, and a carrier or diluent) or differentpharmaceutical formulations (e.g., a first pharmaceuticalcomposition—comprising compounds of formula (I) and a carrier ordiluent; and a second pharmaceutical composition—comprising β-lactamaseinhibitors and a carrier or diluent). When administered in differentformulations, the first and second pharmaceutical compositions may beadministered simultaneously, sequentially, or separated in time.

In other embodiments, the use, in the manufacture of a medicament, of acompound of formula (I) as an active ingredient is provided, wherein theactive ingredient may be provided in an antibacterial composition inadmixture with a carrier. In some embodiments, the use, in themanufacture of a medicament, may further comprise the compound offormula (I) in combination with one or more β-lactamase inhibitors asactive ingredients, in an antibacterial composition in admixture with acarrier. In other embodiments, the use, in the manufacture of amedicament, may further comprise the compound of formula (I) incombination with one or more antibiotics β-lactamase inhibitors asactive ingredients, or in combination with one or more antibiotics(e.g., a β-lactam antibiotic or some other antibiotic) as activeingredients, in an antibacterial composition in admixture with acarrier.

The parenteral administration which includes intramuscular,intraperitonial, subcutaneous and intravenous use, sterile solutions ofthe active ingredients are usually prepared and the pH of the solutionsare suitably adjusted and buffered. For intravenous use, the totalconcentration of solutes should be controlled to render the preparationisotonic. Suitable solvents include saline solution (e.g., 0.9% NaClsolution) and a pyrogenic sterile water. Pharmaceutical compositions fororal delivery can be, for example, in the form of tablets, lozenges,aqueous or oily suspensions, granules, powders, emulsions, capsules,syrups, or elixirs. Orally administered compositions can contain one ormore optional agents, for example, sweetening agents such as fructose,aspartame, or saccharin, flavoring agents such as peppermint, oil ofwintergreen, cherry, coloring agents, and preserving agents to provide apharmaceutically palatable preparation. Moreover, when in tablet form,the compositions can be coated to delay disintegration and absorption inthe gastrointestinal tract, thereby providing a sustained action over anextended period of time. Oral compositions can include standard vehiclessuch as mannitol, lactose, starch, magnesium stearate, sodium saccharin,cellulose, magnesium carbonate, and the like. For oral liquidpreparations, for example, suspensions, elixirs, and solutions, suitablecarriers, excipients, or diluents include water, saline, alkyleneglycols(e.g. propylene glycol), polyalkylene glycols (e.g., polyethyleneglycol), oils, alcohols, slightly acidic buffers ranging from about pH 4to about pH 6 (e.g., acetate, citrate, ascorbate ranging from about 5 mMto about 50 mM), and the like. Additionally, flavoring agents,preservatives, coloring agents, bile salts, acylcarnitines, and the likecan be added.

For topical formulations of the present compounds, creams, gels,ointments or viscous lotions can be used as appropriate delivery forms.Topical delivery systems also include transdermal patches containing atleast one compound of formula (I) to be administered. Delivery throughthe skin can be achieved by diffusion or by more active energy sourcessuch as iontophoresis or electrotransport. Formulations of a compoundherein, for topical use, such as in creams, ointments, and gels, caninclude an oleaginous or water soluble ointment base, for example,topical compositions can include vegetable oils, animal fats, and incertain embodiments, semisolid hydrocarbons obtained from petroleum.Topical compositions can further include white ointment, yellowointment, cetyl esters wax, oleic acid, olive oil, paraffin, petrolatum,white petrolatum, spermaceti, starch glycerite, white wax, yellow wax,lanolin, and glyceryl monostearate. Various water-soluble ointment basescan also be used, including glycol ethers and derivatives, polyethyleneglycols, polyoxyl 40 stearate, and polysorbates.

In a pharmaceutical composition containing the present cephem compounds,the weight ratio of active ingredient to carrier will normally be in therange of 1:20 to 20:1.

The therapeutically effective amount of the compounds of formula (I) andpharmaceutically acceptable salts thereof and the amounts sufficient toachieve the stated goals of the methods disclosed herein vary dependingupon the physical characteristics of the subject, the severity of thesubject's symptoms, the formulation and the means used to administer thedrug, and the method being practiced. The specific dose for a givensubject is usually set by the judgment of the attending physician.However, a therapeutically effective and/or sufficient amount of thecompounds and salts of the present compositions is typically betweenabout 1 mg/kg body weight to 500 mg/kg body weight, including from 1 to100 mg/kg, from 1 to 75 mg/kg, from 1 to 50 mg/kg, from 1 to 25 mg/kg,from 25 to 150 mg/kg, from 25 to 125 mg/kg, from 25 to 100 mg/kg, from25 to 75 mg/kg, from 25 to 50 mg/kg, from 50 to 150 mg/kg, from 50 to125 mg/kg, and from 50 to 100 mg/kg, regardless of the formulation. Inequally preferred aspects, a therapeutically effective amount is about1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or 35 mg/kg bodyweight, regardless of the formulation. In some situations, a dose lessthan 1 mg/kg body weight or greater than 500 mg/kg body weight may beeffective.

In a particular oral formulation for use in the present methods, thecompound of formula (I) or a pharmaceutically acceptable salt thereofmay be in the form of a capsule containing the compound or salt.Suitable amounts of the compound or salt may range from about 10 toabout 3000 mg, with preferred amounts including about 100, 125, 150,175, 200, 225, 250, 275, 300, 350, 400, 450, 500, 550, 600, 650, 700,750, 800, 850, 900, 950, 1000, 1050, 1100, 1150, 1200, 1250, 1300, 1350,1400, 1450 and 1500 mg.

In a particular intravenous (IV) formulation for use in the presentmethods, the compound of formula (I) or a pharmaceutically acceptablesalt thereof is administered in a dosage of between about 100 mg and2000 mg, preferably about 100, 125, 150, 175, 200, 225, 250, 275, 300,325, 350, 375, 400, 450, 500, 600, 700, 800, 900, 1000, 1100, 1200,1300, 1400, 1500 or more mg, by IV infusion over approximately 60, 90,120 or more minutes, every 6, 12, 18 or 24 hours for 1, 2, 3, 4, 5, 6,7, 8, 9, 10 or more days. The compound of formula (I) or apharmaceutically acceptable salt thereof may be reconstituted in sterilewater for injection (WFI) or be diluted in 5% dextrose in water, forexample.

The terms “dose”, “unit dose”, “unit dosage”, or “effective dose” referto physically discrete units that contain a predetermined quantity ofactive ingredient calculated to produce a desired therapeutic effect.These terms are synonymous with the therapeutically effective amountsand amounts sufficient to achieve the stated goals of the methodsdisclosed herein.

‘Therapeutically effective amount’ refers to the amount of a compoundthat, when administered to a subject for treating a disease, or at leastone of the clinical symptoms of a disease, is sufficient to affect suchtreatment of the disease, disorder, or symptom. The therapeuticallyeffective amount can vary depending, for example, on the compound, thedisease, disorder, and/or symptoms of the disease, severity of thedisease, disorder, and/or symptoms of the disease, the age, weight,and/or health of the patient to be treated, and the judgement of theprescribing physician.

Administration frequencies of doses for the treatment of a bacterialinfection include 4, 3, 2 or once daily, every other day, every thirdday, every fourth day, every fifth day, every sixth day, once weekly,every eight days, every nine days, every ten days, bi-weekly, monthlyand bi-monthly. Depending on the means of administration, the dosage maybe administered all at once, such as with an oral formulation in acapsule, or slowly over a period of time, such as with an intravenousadministration. For slower means of administration, the administeringperiod can be a matter of minutes, such as about 5, 10, 15, 20, 25, 30,35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115,120 or more minutes, or a period of hours, such as about 0.5, 1, 1.5, 2,2.5, 3, 3.5, 4, 4.5, 5 or more hours.

The weight ratio of (i) the present compounds and (ii) a β-lactamaseinhibitor or an antibiotic (if it is being administered with aβ-lactamase inhibitor or an antibiotic, e.g., a β-lactam antibiotic orsome other antibiotic) will normally be in the range from about 1:20 toabout 20:1.

In some embodiments, it is an aim to provide an improved method for thetreatment of bacterial infections caused by β-lactamase producingbacteria in a patient in need of such treatment comprising administeringto the patient a therapeutically effective amount of at least onecompound chosen from formula (I) or a pharmaceutically acceptable saltthereof, either alone or in combination with one or more β-lactamaseinhibitors, including the β-lactamase inhibitor of formula (II) to (VII)provided above. In such an embodiment, the compounds may increase theantibacterial effectiveness of β-lactamase susceptible β-lactamantibiotics, that is, they may increase the effectiveness of theantibiotic against infections caused by β-lactamase producingmicro-organisms in mammalian subjects, particularly in humans. As such,the present compounds of formula (I) and pharmaceutically acceptablesalts thereof may valuable for co-administration with β-lactamaseinhibitors. In this regard, the present compounds of formula (I) or apharmaceutically salt thereof can be mixed with the β-lactamaseinhibitors, and the two agents thereby administered simultaneously.Alternatively, the two agents can be administered sequentially, eitherone immediately after the other or separated in time by 1, 5, 10, 15,30, 45 or 60 minutes, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18 or more hours, or 1, 2, 3, 4, 5 or more days. Whenco-administered with a β-lactamase inhibitor, the present compounds andthe β-lactamase inhibitor may, in combination, provide a synergisticeffect. The term ‘synergystic effect’ refers to the effect produced whentwo or more agents are co-administered is greater than the effectproduced when the agents are administered individually. Alternatively,the compound of formula (I) or a salt thereof can be administered as aseparate agent during a course of treatment with the β-lactamaseinhibitor.

In other embodiments, it is an aim to provide an improved method for thetreatment of bacterial infections caused by β-lactamase producingbacteria in a patient in need of such treatment comprising administeringto the patient a therapeutically effective amount of at least onecompound chosen from formula (I) or a pharmaceutically acceptable saltthereof, either alone or in combination with one or more antibiotics,including β-lactam antibiotics and non β-lactam antibiotics. In such anembodiment, the compounds may increase the antibacterial effectivenessof β-lactamase susceptible β-lactam antibiotics, that is, they mayincrease the effectiveness of the antibiotic against infections causedby β-lactamase producing microorganisms in mammalian subjects,particularly in human. In that regard, the compounds of formula (I) andpharmaceutically acceptable salts thereof may be valuable forco-administration with β-lactam antibiotics. In the treatment of abacterial infection, the present so compounds of formula (I) or apharmaceutically salt thereof can be mixed with the β-lactam antibiotic,and the two agents thereby administered simultaneously. Alternatively,the two agents can be administered sequentially, either one immediatelyafter the other or separated in time by 1, 5, 10, 15, 30, 45 or 60minutes, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18 or more hours, or 1, 2, 3, 4, 5 or more days. When co-administeredwith a β-lactam antibiotic, the combination of the present compound andthe antibiotic can provide a synergistic effect. The term ‘synergysticeffect’ refers to the effect produced when two or more agents areco-administered is greater than the effect produced when the agents areadministered individually. Alternatively, the compound of formula (I) ora salt thereof can be administered as a separate agent during a courseof treatment with the antibiotic. Examples of compounds of the formula(I), without limiting to the specified compounds, are provided in thefollowing Table 1.

TABLE 1 Com- pound No. Structure Chemical Name 1

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4- yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}- 3-{[1-(4-carbamimidoylbenzyl)-1H-pyrrolo[3,2-c]pyridin- 5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2- ene-2-carboxylate 2

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4-yl)-2-{[(2- carboxypropan-2-yl)oxy]imino}acetyl]- amino}-8-oxo-3-[(1- {4-[N-(piperidin-3-yl)carbamimidoyl]- benzyl}-1H-pyrazolo[4,3-c]pyridin-5-ium-5-yl)methyl]- 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 3

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4-yl)-2-{[(2-car-boxypropan-2-yl)oxy]imino}- acetyl]amino}-8-oxo-3-[(1-{4-[N-(piperidin-3- yl)carbamimidoyl]benzyl}- 1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl)methyl]-5-thia-1- azabicyclo[4.2.0]oct-2- ene-2-carboxylate 4

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]- imino}acetyl]amino}-3-{[1-(4-carbamimidamidobenzyl)-1H- pyrrolo[3,2-c]pyridin-5-ium-5-yl]methyl}-8-oxo-5-thia- 1-azabicyclo[4.2.0]oct-2- ene-2-carboxylate 5

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4- yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}- 3-{[1-(4- carbamimidoylbenzyl)-1H-imidazo[1,2- b]pyrazol-5-ium-5-yl]methyl}- 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene- 2-carboxylate 6

(6R,7S)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4- yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}- 3-({1-[4-(2- carbamimidamidoethoxy)-benzyl]-1H- pyrrolo[3,2-c]pyridin-5- ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo- [4.2.0]oct-2-ene-2-carboxylate 7

(6R,7R)-3-[(1-{4-[N-(2- aminoethyl)carbamimidoyl]- benzyl}-1H-pyrrolo[3,2-c]pyridin-5-ium- 5-yl)methyl]-7-{[(2Z)-2-(2-amino-1,3-thiazol- 4-yl)-2-{[(2- carboxypropan-2-yl)oxy]imino}acetyl]amino}- 8-oxo-5-thia- 1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 8

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4- yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}- 3-({1-[4-(4,5- dihydro-1H-imidazol-2-yl)benzyl]-1H- pyrrolo[3,2-c]pyridin-5- ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo- [4.2.0]oct-2-ene-2-carboxylate 9

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4- yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}- 3-{[1-(4- carbamimidoylbenzyl)-2,3-dihydro-1H- imidazo[1,2-b]pyrazol-5-ium- 5-yl]methyl}-8-oxo-5-thia-1-azabicyclo- [4.2.0]oct-2-ene-2-carboxylate 10

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4- yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}- 3-({1-[4-(2- carbamimidamidoethoxy)-benzyl]-2,3- dihydro-1H-imidazo[1,2- b]pyrazol-5-ium-5-yl}methyl)-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene- 2-carboxylate 11

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4- yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}- 3-({1-[(4- carbamimidoylthiophen-2-yl)methyl]-1H- pyrrolo[3,2-c]pyridin-5-ium- 5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]- oct-2-ene-2-carboxylate 12

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4- yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3- ({1-[2-(4- carbamimidamidophenyl)ethyl]-1H-pyrrolo[3,2-c]pyridin-5- ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]- oct-2-ene-2-carboxylate 13

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4- yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}- 3-({1-[(4- carbamimidoylfuran-2-yl)methyl]-1H- pyrrolo[3,2-c]pyridin-5-ium- 5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]- oct-2-ene-2-carboxylate 14

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4- yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}- 3-{[1-(4- carbamimidoyl-2-fluorobenzyl)-1H-pyrrolo[3,2-c]pyridin-5- ium-5-yl]methyl}- 8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylate 15

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4- yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}- 3-{[1-(4- carbamimidoyl-2-fluorobenzyl)-1H-imidazo[1,2-b]pyrazol-5- ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]- oct-2-ene-2-carboxylate 16

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4- yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}- 3-([1-[(4- carbamimidoyl-1,3-thiazol-2-yl)methyl]-1H- pyrrolo[3,2-c]pyridin-5-ium- 5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2- ene-2-carboxylate 17

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4- yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}- 3-{[1-({3- [(diaminomethylidene)amino]-1,2-oxazol-5- yl}methyl)-1H-pyrrolo[3,2- c]pyridin-5-ium-5-yl]methyl}-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2- carboxylate18

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4- yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}- 3-({1-[(4- carbamimidoylthiophen-2-yl)methyl]-1H- imidazo[1,2-b]pyrazol-5-ium- 5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]- oct-2-ene-2-carboxylate 19

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4- yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}- 3-({1-[4-(N′- methoxycarbamimidoyl)benzyl]-1H-pyrrolo[3,2-c]pyridin-5- ium-5-yl}methyl)- 8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylate 20

(6R,7R)-7-{[(2Z)-2-(5-amino- 1,2,4-thiadiazol-3-yl)-2-{[(2-carboxypropan-2- yl)oxy]imino}acetyl]amino}- 3-{[1-(4-carbamimidoyl-2-fluorobenzyl)- 1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl]methyl}- 8-oxo-5-thia-1-azabicyclo- [4.2.0]oct-2-ene-2-carboxylate 21

(6R,7R)-7-{[(2Z)-2-(2-amino- 5-chloro-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2- yl)oxy]imino}acetyl]amino}-3-{[1-(4-carbamimidoyl-2- fluorobenzyl)-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl]methyl}- 8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene- 2-carboxylate 22

(6R,7R)-7-({(2Z)-2-(2-amino- 1,3-thiazol-4- yl)-2-[(carboxymethoxy)-imino]acetyl}amino)- 3-{[1-(4-carbamimidoyl-2-fluorobenzyl)-1H-imidazo[1,2- b]pyrazol-5-ium-5-yl]methyl}-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene- 2-carboxylate 23

(6R,7R)-7-{[(2Z)-2-(2-amino-5- chloro-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2- yl)oxy]imino}acetyl]amino}-3-{[1-(4-carbamimidoyl-2- fluorobenzyl)-1H-imidazo[1,2-b]pyrazol-5-ium-5-yl]methyl}- 8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene- 2-carboxylate 24

(6R,7R)-7-{[(2Z)-2-(5-amino- 1,2,4-thiadiazol-3-yl)-2-{[(2-carboxypropan-2- yl)oxy]imino}acetyl]amino}- 3-{[1-(4-carbamimidoyl-2-fluorobenzyl)-1H- imidazo[1,2-b]pyrazol-5-ium- 5-yl]methyl}-8-oxo-5-thia-1-azabicyclo- [4.2.0]oct-2-ene- 2-carboxylate 25

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4- yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}- 3-({1-[(4- carbamimidoylfuran-2-yl)methyl]-1H- imidazo[1,2-b]pyrazol-5-ium- 5-yl}methyl)-8-oxo-5-thia-1-azabicyclo- [4.2.0]oct-2-ene- 2-carboxylate 26

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4- yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}- 3-({1-[(4- carbamimidoyl-1,3-thiazol-2-yl)methyl]- 1H-imidazo[1,2-b]pyrazol-5- ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct- 2-ene-2-carboxylate 27

(6R,7R)-7-{[(2Z)-2-(5-amino- 1,2,4-thiadiazol-3-yl)-2-{[(2-carboxypropan-2- yl)oxy]imino}acetyl]amino}- 3-({1-[(4-carbamimidoylthiophen-2- yl)methyl]-1H- imidazo[1,2-b]pyrazol-5-ium-5-yl}methyl)- 8-oxo-5-thia-1-azabicyclo- [4.2.0]oct-2-ene-2-carboxylate 28

(6R,7R)-7-{[(2Z)-2-(2-amino 5-chloro-1,3-thiazol-4-yl)-2-{([(2-carboxypropan-2-yl)oxy]- imino}acetyl]amino}-3-({1-[(4-carbamimidoylthiophen-2- yl)methyl]-1H-imidazo[1,2-b]pyrazol-5-ium-5-yl}methyl)- 8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene- 2-carboxylate 29

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4-yl)-2-{[(2-car-boxypropan-2-yl)oxy]imino} acetyl]-amino}-3-[(1-{[3-(4,5-dihydro-1H-imidazol-2-yl)- 1,2-oxazol-5-yl]methyl}-1H-pyrrolo[3,2-c]pyridin-5-ium- 5-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene- 2-carboxylate 30

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4-yl)-2-{[(2-car-boxypropan-2-yl)oxy]imino}- acetyl]amino}-3-({1-[(4-carbamimidoyl-1,3-oxazol- 2-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl}methyl)- 8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylate 31

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4-yl)-2-{[(2- carboxypropan-2-yl)oxy]imino}acetyl]amino}-3- ({1-[(4-{N-[(E)-(dimethylamino)methylidene] carbamimidoyl}-1,3-oxazol-2-yl)methyl]-1H-pyrrolo[3,2- c]pyridin-5-ium-5-yl}methyl)-8-oxo-5-thia-1- azabicyclo[4.2.0] oct-2-ene-2-carboxylate 32

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4-yl)-2-{[(2- carboxypropan-2-yl)oxy]imino}acetyl]aminol- 3-{[1-({2-[(diamino-methylidene)amino]-1,3-thiazol- 4-yl}methyl)-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl]methyl}- 8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylate 33

(6R,7R)-7-{[(2Z)-2-(2-amino-5- chloro-1,3-thiazol-4-yl)-2-(hydroxyimino)acetyl]amino)- 3-({1-[(4-carbamimidamidothio-phen-2-yl)methyl]-1H- imidazo[1,2-b]pyrazol-5-ium-5-yl}methyl)-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene- 2-carboxylate34

(6R,7R)-7-{[(2Z)-2-(2-amino-5- chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}- 3-({1-[(4-carbamimidamidothio-phen-2-yl)methyl]-1H- imidazo[1,2-b]pyrazol-5-ium-5-yl}methyl)-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene- 2-carboxylate 35

(6R,7R)-7-{[(2Z)-2-(2-amino-5- chloro-1,3-thiazol-4-yl)-2-(hydroxyimino)acetyl]amino}- 3-({1-[(4-carbamimidamido-1,3-thiazol-2-yl)methyl]-1H- imidazo[1,2-b]pyrazol-5-ium-5-yl}methyl)-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene- 2-carboxylate 36

(6R,7R)-7-{[(2Z)-2-(2-amino-5- chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}- 3-({1-[(4-carbamimidamido-1,3-thiazol-2-yl)methyl]- 1H-imidazo[1,2-b]pyrazol-5-ium-5-yl}methyl)-8-oxo-5- thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 37

(6R,7R)-7-{[(2Z)-2-(2-amino- 5-chloro-1,3-thiazol-4-yl)-2-(hydroxyimino)acetyl]amino}- 3-{[1-(4-carbamimidamido-benzyl)-1H-imidazo[1,2- b]pyrazol-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo- [4.2.0]oct-2-ene-2-carboxylate 38

(6R,7R)-7-{[(2Z)-2-(2-amino-5- chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}- 3-([1-(4-carbamimidamido-benzyl)-1H-imidazo[1,2- b]pyrazol-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]- oct-2-ene-2-carboxylate 39

(6R,7R)-1-{[(2Z)-2-(2-amino-5- chloro-1,3-thiazol-4-yl)-2-(hydroxyimino)acetyl]amino)- 3-({1-[(4-carbamimidamido-furan-2-yl)methyl]-1H- imidazo[1,2-b]pyrazol-5-ium-5-yl}methyl)-8-oxo-5- thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 40

(6R,7R)-7-{[(2Z)-2-(2-amino- 5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}- 3-({1-[(4-carbamimidamido-furan-2-yl)methyl]-1H-imi- dazo[1,2-b]pyrazol-5-ium-5-yl}methyl)-8-oxo-5-thia-1- azabicyclo-[4.2.0]oct-2-ene- 2-carboxylate 41

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4- yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}- 3-({1-[(4- carbamimidamidothiophen-2-yl)methyl]- 1H-imidazo[1,2-b]pyrazol- 5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct- 2-ene-2-carboxylate 42

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4- yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}- 3-({1-[(4-carbamimidamido-1,3-thiazol-2-yl)methyl]- 1H-imidazo[1,2-b]pyrazol-5-ium-5-yl}methyl)-8-oxo- 5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 43

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4-yl)-2-{[(2- carboxypropan-2-yl)oxy]imino]acetyl]amino}- 3-{[1-(4-carbamimidamido-benzyl)-1H-imidazo[1,2- b]pyrazol-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]- oct-2-ene-2-carboxylate 44

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4- yl)-2-{[(2-carboxypropan-2-yl)oxy]imino)acetyl]amino}- 3-({1-[(4- carbamimidamidofuran-2-yl)methyl]-1H- imidazo[1,2-b]pyrazol-5-ium- 5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene- 2-carboxylate 45

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4- yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}- 3-({1-[4- (hydrazinylcarbonoimidoyl)-benzyl]-1H- pyrrolo[3,2-c]pyridin-5-ium-5- yl}methyl)-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2- ene-2-carboxylate 46

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]- imino}acetyl]amino}-3- {[1-(3-carbamimidamido-propyl)-1H-imidazo[1,2- b]pyrazol-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo- [4.2.0]oct-2-ene-2-carboxylate 47

(6R,7R)-7-{[(2Z)-2-(2-amino- 5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}- 3-{[1-(3-carbamimidamido-propyl)-1H-imidazo[1,2- b]pyrazol-5-ium-5-yl]methyl}- 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene- 2-carboxylate 48

(6R,7R)-7-{[(2Z)-2-(2-amino-5- chloro-1,3-thiazol-4-yl)-2-(hydroxyimino)acetyl]amino}- 3-{[1-(3- carbamimidamidopropyl)-1H-imidazo[1,2- b]pyrazol-5-ium-5-yl]methyl}- 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene- 2-carboxylate 49

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4- yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}- 3-{[1-(4- carbamimidoyl-2-chloro-6-fluorobenzyl)-1H-pyrrolo[3,2- c]pyridin-5-ium-5-yl]methyl}-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2- carboxylate 50

(6R,7R)-7-{[(2Z)-2-(2-amino- 5-chloro-1,3- thiazol-4-yl)-2-(methoxyimino)acetyl]amino}- 3-({1-[(4- carbamimidoylthiophen-2-yl)methyl]-1H- pyrrolo[3,2-c]pyridin-5-ium- 5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene- 2-carboxylate 51

(6R,7R)-7-{[(2Z)-2-(2-amino- 5-chloro-1,3- thiazol-4-yl)-2-(methoxyimino)acetyl]amino)- 3-({1-[(4- carbamimidoylthioplien-2-yl)methyl]-1H- imidazo[1,2-b]pyrazol-5-ium- 5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene- 2-carboxylate 52

(6R,7R)-7-{[(2Z)-2-(2-amino- 5-chloro-1,3- thiazol-4-yl)-2-(methoxyimino)acetyl]amino}- 3-{[1-(4- carbamimidoyl-2-fluorobenzyl)-1H-pyrrolo[3,2-c]pyridin-5- ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene- 2-carboxylate 53

(6R,7R)-7-{[(2Z)-2-(2-amino-5- chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]- amino}-3-({1-[(4- carbamimidoyl-1,3-thiazol-2-yl)methyl]- 1H-imidazo[1,2-b]pyrazol- 5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct- 2-ene-2-carboxylate 54

(6R,7R)-7-{[(2Z)-2-(2-amino- 5-chloro-1,3- thiazol-4-yl)-2-(methoxyimino)acetyl]amino}- 8-oxo-3-{[1- (4-{N-[(3R)-piperidin-3-yl]carbamimidoyl}benzyl)-1H- pyrrolo[3,2- c]pyridin-5-ium-5-yl]methyl}-5-thia-1-azabicyclo[4.2.0]oct- 2-ene-2-carboxylate 55

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}- 3-{[1-(4-carbamimidoyl-2- fluorobenzyl)-1H-pyrrolo[3,2-c]pyridin-5-ium- 5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene- 2-carboxylate 56

(6R,7R)-7-{[(2Z)-2-(2-amino- 5-chloro-1,3- thiazol-4-yl)-2-(methoxy-imino)acetyl]amino}- 3-({1-[(4-carbamimidoyl- furan-2-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-5-ium- 5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene- 2-carboxylate 57

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4- yl)-2-{[(2-carboxypropan-2-yl)oxy]imino)acetyl]amino}- 3-{[1-({3-[(diaminomethyli-dene)amino]-1,2-oxazol-5- yl}methyl)-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl]methyl}- 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene- 2-carboxylate 58

(6R,7R)-7-{[(2Z)-2-(2-amino- 5-chloro-1,3- thiazol-4-yl)-2-(methoxyimino)acetyl]amino}- 3-{[1-(4- carbamimidoyl-2-chloro-6-fluorobenzyl)- 1H-pyrrolo[3,2-c]pyridin- 5-ium-5-yl]methyl}-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene- 2-carboxylate 59

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4- yl)-2-(methoxyimino)acetyl]-amino}-3-({1- [(4-carbamimidoylthiophen- 2-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-5- ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2- ene-2-carboxylate 60

(6R,7R)-7-{[(2Z)-2-(2-amino- 5-chloro-1,3- thiazol-4-yl)-2-(methoxyimino)acetyl]amino}- 3-({1-[(4-carbamimidoylthio-phen-2-yl)methyl]-1H- pyrrolo[3,2-b]pyridin-4-ium-4- yl}methyl)-8-oxo-5-thia-1-azabicyclo- [4.2.0]oct-2-ene- 2-carboxylate 61

(6R,7R)-7-{[(2Z)-2-(2-amino-5- chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}- 3-({1-[(4-carbamimidoylthio-phen-2-yl)methyl]-1H- pyrrolo[2,3-c]pyridin-6- ium-6-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2- ene-2-carboxylate 62

Preparation of (6R,7R)-7- {[(2Z)-2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2- (methoxyimino)acetyl]amino}-8-oxo-3-[(1-{[4-(N-phenylcar- bamimidoyl)thiophen-2-yl]methyl}-1H-pyrrolo[3,2- c]pyridin-5-ium- 5-yl)methyl]-5-thia-1-azabicyclo[4.2.0]oct- 2-ene-2-carboxylate 63

(6R,7R)-7-{[(2Z)-2-(2-amino- 5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}- 8-oxo-3-[(1-([4-(pyrrolidin-1-ylcarbonoimidoyl)thiophen- 2-yl]methyl}-1H-pyrrolo[3,2-c]pyridin-5-ium-5- yl)methyl]-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylate 64

(6R,7R)-7-{[(2Z)-2-(2-amino- 5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}- 8-oxo-3-{[1-({4-[N-(1,3-triazol-2-yl)carbamimidoyl]- thiophen-2-yl}methyl)-1H- pyrrolo[3,2-c]pyridin-5-ium-5-yl]methyl}- 5-thia-1-azabicyclo[4.2.0]cot-2-ene-2-carboxylate 65

(6R,7R)-7-{[(2Z)-2-(2-amino- 5-chloro-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2- yl)oxy]imino}acetyl]amino}- 3-({1-[(4-carbamimidoylthiophen-2- yl)methyl]-1H-pyrrolo[2,3-c]pyridin-6-ium-6-yl}methyl)- 8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene- 2-carboxylate 66

(6R,7R)-7-{[(2Z)-2-(5-amino- 1,2,4-thiadiazol-3-yl)-2-{[(2-carboxypropan-2-yl)oxy] imino}acetyl]amino}-3-({1-[(4-carbamimidoylthiophen- 2-yl)methyl]-1H-pyrrolo[2,3-c]pyridin-6-ium-6-yl}methyl)- 8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene- 2-carboxylate 67

(6R,7R)-7-{[(2Z)-2-(5-amino- 1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetyl]amino}- 3-({1-[(4-carbamimidoylthio-phen-2-yl)methyl]-1H- pyrrolo[2,3-c]pyridin-6-ium-6-yl}methyl)-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene- 2-carboxylate68

(6R,7R)-7-{[(2Z)-2-(5-amino- 1,2,4-thiadiazol-3-yl)-2-{[(2-carboxypropan-2- yl)oxy]imino}acetyl]amino}-3-({1-[(4-carbamimidoylthio- phen-2-yl)methyl]-1H-pyrrolo[3,2-b]pyridin-4-ium- 4-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene- 2-carboxylate 69

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazo]-4-yl)-2-(methoxy-imino)acetyl]amino}-3-{[1- (4-carbamimidoyl-2-chloro-6-fluorobenzyl)-1H-pyrrolo[3,2- c]pyridin-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo- [4.2.0]oct-2-ene-2-carboxylate 70

(6R,7R)-7-{[(2Z)-2-(2-amino- 5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino)- 3-{[1-(4-carbamimidoyl-2-chloro-6-fluorobenzyl)- 1H-pyrrolo[2,3-c]pyridin-6-ium-6-yl]methyl}-8-oxo-5-thia- 1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 71

(6R,7R)-7-{[(2Z)-2-(2-amino- 5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}- 3-{[1-(4-carbamimidoyl-2-chloro-6-fluorobenzyl)- 1H-pyrrolo[3,2-b]pyridin-4-ium-4-yl]methyl}-8-oxo-5- thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylate 72

(6R,7R)-7-{[(2Z)-2-(2-amino- 5-chloro-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2- yl)oxy]imino}acetyl]amino}-3-{[1-(4-carbamimidoyl-2- chloro-6-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridin- 6-ium-6-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct- 2-ene-2-carboxylate 73

(6R,7R)-7-{[(2Z)-2-(2-amino- 1,3-thiazol-4-yl)-2-(methoxy-imino)acetyl]amino}-3-{[1- (4-carbamimidoyl-2-chloro-6-fluorobenzyl)-1H-pyrrolo[2,3- c]pyridin-6-ium-6-yl]methyl}-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene- 2-carboxylate 74

(6R,7R)-7-{[(2Z)-2-(5-amino- 1,2,4-thiadiazol-3-yl)-2-{[(2-carboxypropan-2-yl)oxy]- imino}acetyl]amino}-3-{[1-(4-carbamimidoyl-2-chloro-6- fluorobenzyl)-1H-pyrrolo[2,3-c]pyridin-6-ium-6-yl]methyl}- 8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylateMethods of Preparation:

The compounds of general formula (I) can be prepared as described in thefollowing schemes (Scheme 1 and Scheme 2) which illustrate the generalmethod of preparation only and are not intended to be limiting to anyspecific compound described herein.

Process I (Scheme 1):

(a) Coupling Step:

Reaction of (VIII, q=0, Y=chloride) with the intermediate (IX) iscarried out in a conventional solvent such as water, alcohol (e.g.,methanol, ethanol etc.), acetone, dioxane, acetonitrile, chloroform,methylene chloride, ethylene chloride, tetrahydrofuran, ethylacetate,N,N-dimethylformamide, pyridine or any other organic solvent which doesnot adversely influence the reaction. These conventional solvents mayalso be used as a co-solvent in a mixture with water. In this reaction,when Y=Cl, the reaction is preferably carried out in the presence of aconventional alkali metal halide such as potassium iodide and in thepresence of N,N-dimethylformamide or dimethylacetamide. The reaction isusually carried out ranging from −20° C. to 40° C.

(b) Hydrolysis Step:

The hydrolysis is preferably carried out in the presence of a base or anacid including Lewis acid. Suitable base may include an inorganic basesuch as an alkali metal (e.g., sodium, potassium etc.); an alkali earthmetal (e.g., magnesium, calcium etc.), the hydroxide or carbonate orbicarbonate thereof, and an organic base trialkylamine (e.g.,trimethylamine, triethylamine, etc.), picoline or the like. Suitableacid may include an organic acid (e.g., formic acid, acetic acid,propionic acid, trichloroacetic acid, trifluoroacetic acid) and aninorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuricacid). The hydrolysis using Lewis acid such as trihaloacetic acid (e.g.,trichloroacetic acid, trifluoroacetic acid) or the like and the reactionis preferably carried out in the presence of cation trapping agents(e.g., anisole, phenol etc.). The hydrolysis using Lewis acid such asaluminum trichloride is carried out in a solvent like nitromethane. Thehydrolysis reaction is usually carried out in a non-aqueous solvent suchas methylene chloride, tetrahydrofuran, a mixture of solvents thereof,or any other solvent that does not adversely influence the reaction. Thereaction temperature may be room temperature, or any other temperatureas may be appropriate.

Process II (Scheme 2):

(a) Coupling Step:

Reaction of (VIII, q=1, Y=iodide) with the intermediate (IX) is carriedout in a conventional solvent such as water, alcohol (e.g., methanol,ethanol etc.), acetone, dioxane, acetonitrile, chloroform, methylenechloride, ethylene chloride, tetrahydrofuran, ethyl acetate,N,N-dimethylformamide, pyridine or any other organic solvent which doesnot adversely influence the reaction. These conventional solvents mayalso be used as a co-solvent in a mixture with water. In this reaction,when Y=Cl, the reaction is preferably carried out in the presence of aconventional alkali metal halide such as potassium iodide and in thepresence of N,N-dimethylformamide or dimethylacetamide. The reactiontemperature is not critical, and usually carried out under cooling toroom temperature, even more preferably ranging from −20° C. to 40° C.

(b) Reduction Step:

Reduction is carried out in a conventional manner. Suitable reducingagents to be used in chemical reduction are a combination of a metal(e.g., tin, zinc, iron etc.) and an organic or inorganic acid (e.gformic acid, acetic acid, propionic acid, trifluoroacetic acid,p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).Reduction can also be carried out using a combination of alkali metalhalide (e.g., potassium iodide) and acetyl chloride. The reduction isusually carried out in a conventional solvent which does not adverselyinfluence the reaction such as N,N-dimethylformamide, diethyl ether,dioxane, tetrahydrofuran, etc. or a mixture of solvents thereof. Thereduction is carried out under cooling to warming, more specifically inthe range from −40° C. to 0° C.

(c) Hydrolysis Step:

The hydrolysis is preferably carried out in the presence of a base or anacid including Lewis acid. Suitable base may include an inorganic basesuch as an alkali metal (e.g., sodium, potassium etc.); an alkali earthmetal (e.g., magnesium, calcium etc.), the hydroxide or carbonate orbicarbonate thereof, and an organic base, trialkylamine (e.g.,trimethylamine, triethylamine, etc.), picoline or the like. Suitableacid may include an organic acid (e.g., formic acid, acetic acid,propionic acid, trichloroacetic acid, trifluoroacetic acid) and aninorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuricacid). The hydrolysis using Lewis acid such as trihaloacetic acid (e.g.,trichloroacetic acid, trifluoroacetic acid) or the like and the reactionis preferably carried out in the presence of cation trapping agents(e.g., anisole, phenol etc.). The hydrolysis using Lewis acid such asaluminum trichloride is carried out in a solvent like nitromethane. Thehydrolysis reaction is usually carried out in a non-aqueous solvent suchas methylene chloride, tetrahydrofuran, a mixture of solvents thereof orany other solvent that does not adversely influence the reaction. Thereaction temperature is not critical, but is usually carried out at roomtemperature.

In the formula (VIII), A and B have the same definitions as describedbefore.

Thus, in formula (VIII), A is defined by the formula (Ia);

Object (1a) includes syn isomer (Z form) anti isomer (E form) and amixture thereof.

Wherein X is N, C(H), C(F) or C(Cl);

B is defined as hydrogen, methyl, ethyl or represented by the formula(Ib)

Wherein, R¹ and R² is independently hydrogen or lower alkyl, or R¹ andR² together may form a 3 to 6-membered spiro ring system; and

m is 0 or 1.

Furthermore, in the formula (Ib), R¹ and R² together may form a 3- to6-membered spiro ring system;

Y is halogen, even more preferably chloro or iodo;

q is 0 or 1;

In the organic residue as designated by (IX), objects C, D, E and F havethe same definitions as described before, thus C is selected from thefollowing quaternized bicyclic aromatic heterocyclic rings representedby the formulae (Ic) to (Iz);

D represents CH₂, CH₂CH₂ or CH₂CO;

-   E is selected from aryl or a 5- to 6-membered aromatic heterocyclic    ring as shown below;

F is optionally substituted amidine or an optionally substitutedguanidine; andG is hydrogen, methyl, ethyl, C₃₋₆ alkyl, C₃₋₆ cycloalkyl or anoptionally substituted 5- or 6-membered aliphatic or an optionallysubstituted 5- or 6-membered aromatic heterocyclic ring, in which theheterocyclic ring is substituted with at least 1-2 hetero atoms selectedfrom N, O, and S (α or β).

In the formula (VIII), P¹ is a suitable carboxy protecting groupfrequently used in (3-lactam chemistry. Suitable examples may be theones such as lower alkyl ester (e.g., methyl, ethyl, propyl, isopropyl,butyl, isobutyl, t-butyl, pentyl, t-pentyl, hexyl, 1-cyclopropylethyletc.); lower alkenyl ester (e.g., vinyl, allyl); lower alkynyl ester(e.g., ethynyl, propynyl); lower alkoxyalkyl ester (e.g., methoxymethyl,ethoxymethyl, isopropoxymethyl, 1-methoxyethyl, 1-ethoxyethyl etc.);lower alkylthioalkyl ester (e.g., methylthiomethyl, ethylthiomethyl,ethylthioethyl, isopropylthiomethyl); mono (or di or tri-) halo(lower)alkyl ester (e.g., 2-iodoethyl, 2,2,2-trichloroethyl etc.); loweralkanoyloxy(lower)alkyl ester (e.g., acetoxymethyl, propionyloxymethyl,butyryloxymethyl, valeryloxymethyl, pivaloyloxymethyl,hexanoyloxymethyl, 2-acetoxyethyl, 2-propionyloxyethyl etc.); loweralkanesulfonyl(lower)alkyl ester (e.g., mesylmethyl ester, 2-mesylethylester etc.); ar(lower)alkyl ester, for example, phenyl(lower)alkyl esterwhich may have one or more suitable substituent(s) (e.g., benzyl,4-methoxybenzyl, 4-nitrobenzyl, phenethyl, trityl, benzhydryl,bis(methoxyphenyl)methyl, 3,4-dimethoxybenzyl,4-hydroxy-3,5-di-t-butylbenzyl, etc.); aryl ester which may have one ormore suitable substituent(s) such as substituted or unsubstituted phenylester (e.g., phenyl, tolyl, t-butyl phenyl, xylyl, mesityl,4-chlorophenyl, 4-methoxyphenyl, etc.); tri(lower)alkyl silyl ester;lower alkylthioester (e.g., methylthioester, ethylthioester, etc.) andthe like.

It is understood that in the formula (VIII), when an amino group ispresent in the molecule, it is to be protected with a suitableprotecting group commonly used in the β-lactam chemistry such as benzyl,trityl, t-butoxycarbonyl or the like. Similarly, it is to be understoodthat in the formula (VIII), when a carboxyl group is present in themolecule, it is to be protected with a suitable protecting groupselected from the group as described for P^(I-) above.

The following are provided for illustrative purposes only, and are notintended to be limiting of the present compositions and methods in anyway.

EXAMPLES

In the examples the following abbreviations have been used.

Boc: N-tert-butoxycarbonyl

Br s: broad singlet

CDCl₃: deuterated chloroform

CD₃OD: deuterated methanol

CH₃NO₂: nitromethane

D₂O: deuterium oxide

d: doublet

DCM: dichloromethane

DMAP: 4-dimethylaminopyridine

DMF: N, N′-dimethylformamide

DMSO-d₆: deuterated dimethylsulfoxide

ES: electron spray

g: gram(s)

h: hour(s)

HPLC: high-performance liquid chromatography

Hz: Hertz

J: coupling constant

m: multiplet

mmol: millimole(s)

MHz: megahertz

MS: mass spectrometry

Example 1 (Table 1, Compound 1)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]-amino}-3-{[1-(4-carbamimidoylbenzyl)-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

Step 1: 4-(1H-Pyrrolo[3,2-c]pyridin-1-ylmethyl)benzonitrile

To a solution of 1H-pyrrolo[3,2-c]pyridine (1.0 g, 8.5 mmol) in DMF (40mL) under nitrogen at 0° C. was added NaH (60% in mineral oil, 0.51 g,12.8 mmol) in portions and after stirring for 15 min was added4-(bromomethyl)benzonitrile (2.5 g, 12.8 mmol) in portions. The reactionmixture was stirred at 0° C. for 2 h then at room temperature for 1 hand quenched with saturated ammonium chloride solution then diluted withethyl acetate (100 mL) and water (100 mL). The organic layer wasseparated, washed with brine (3×100 mL), dried (Na₂SO₄) andconcentrated.

The crude product was purified by silica gel column chromatography usingmethylene chloride: ethyl acetate: methanol (5:3:2) to afford4-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)benzonitrile (1.2 g, 60%) as asolid.

¹H NMR (400 MHz, CDCl₃): δ 5.38 (s, 2H), 6.68 (d, 1H, J=3.2 Hz),7.11-7.17 (m, 4H), 7.54 (d, 2H, J=8.0 Hz), 8.27 (d, 1H, J=5.6 Hz), 8.94(s, 1H).

Step 2: Methyl4-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)benzenecarboximidatehydrochloride

Through a solution of4-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)benzonitrile (from step 1, 0.7 g,3.0 mmol) in anhydrous methanol (25 mL) in a pressure vessel at 0° C.was bubbled a stream of anhydrous hydrogen chloride gas for 10 min. Thereaction vessel was stoppered and stirred at room temperature for 18 hand the contents were transferred into a flask and evaporated underreduced pressure. The crude product was triturated with ether, thendried under vacuum to provide methyl4-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)benzenecarboximidatehydrochloride (0.85 g, 94%) as a solid.

¹H NMR (400 MHz, CD₃OD): δ 4.34 (s, 3H), 5.50 (s, 2H), 7.20 (s, 1H),7.50 (d, 2H, J=8.0 Hz), 7.96-8.11 (m, 4H), 8.39 (d, 1H, J=6.8 Hz), 9.22(s, 1H). One proton was not observed in CD₃OD.

Step 3: 4-(1H-Pyrrolo[3,2-c]pyridin-1-ylmethyl)benzenecarboximidamide

A pressure vessel containing a suspension of methyl4-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)benzenecarboximidatehydrochloride (from step 2, 0.9 g, 2.85 mol) in methanol (25 mL) wassaturated with ammonia gas and stoppered. The reaction mixture wasstirred at room temperature for 24 h, then excess ammonia was vented outand the contents were concentrated under reduced pressure. The residuewas triturated with hexanes and dried under vacuum to give4-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)benzenecarboximidamide (1.0 g) asa solid.

¹H NMR (400 MHz, CD₃OD): δ 5.76 (s, 2H), 7.05 (d, 1H, J=3.2 Hz), 7.45(d, 2H, J=8.0 Hz), 7.79-7.89 (m, 4H), 8.30 (s, 1H), 9.08 (s, 1H). Threeprotons were not observed in CD₃OD.

Step 4: tert-Butyl{[4-(1H-pyrrolo[3,2-c]pyridinylmethyl)phenyl]carbonoimidoyl}carbamate

A solution of4-(1H-Pyrrolo[3,2-c]pyridin-1-ylmethyl)benzenecarboximidamide (from step3, 0.25 g. 1.0 mmol) in 1,4-dioxane (30 mL) was treated with a saturatedsodium carbonate solution (20 mL) followed by di-tert-butyl dicarbonate(1.1 g, 5.0 mmol) and stirred at room temperature for 40 h. The reactionmixture was concentrated under reduced pressure to remove the volatilesand the remaining solution was dissolved in ethyl acetate (60 mL), thenwashed with water (60 mL), brine solution (60 mL), dried andconcentrated. The crude product was purified by silica gel columnchromatography using ethyl acetate:methanol:ammonium hydroxide (60:39:1)as eluent to afford tert-butyl{[4-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)phenyl]carbonoimidoyl}carbamate(0.12 g, 34%).

¹H NMR (400 MHz, CDCl₃): δ 1.54 (s, 9H), 5.36 (s, 2H), 6.60 (br s, 1H),6.66 (d, 1H, J=3.6 Hz), 7.11-7.14 (m, 5H), 7.79 (d, 2H, J=8.4 Hz), 8.23(d, 1H, J=6.0 Hz), 8.93 (s, 1H).

Step 5:5-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-Butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-{[(1-tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy]imino}acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-ylmethyl}-1-{4-[N-(tert-butoxycarbonyl)carbamimidoyl]benzyl}-1H-pyrrolo[3,2-c]pyridin-5-iumiodide

To a solution of tert-butyl{[4-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)phenyl]carbonoimidoyl}carbamate(from step 4, 0.07 g, 0.20 mmol) in dimethylacetamide (1.3 mL) was added4-methoxybenzyl(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-{[(1-tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy]imino}acetyl]amino}-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate(0.156 g, 0.20 mmol) at 0° C. The reaction mixture was then degassedunder reduced pressure for 0.5 h and was added sodium iodide (0.06 g,0.40 mmol). After stirring at 15° C. for 16 h, the reaction mixture wasslowly added to 5% aqueous sodium chloride and sodium thiosulfatesolution cooled under ice. The suspension was then filtered, washed withwater and the solid was vacuum dried to get a yellow solid (0.22 g)which was used in the next step without further purification.

Step 6:(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-{[1-(4-carbamimidoylbenzyl)-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

To a solution of5-{[(6R,7R)-7-{[(2Z)-2-{5-[(tert-butoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl}-2-{[(1-tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy]imino}acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-{4-[N-(tert-butoxycarbonyl)carbamimidoyl]benzyl}-1H-pyrrolo[3,2-c]pyridin-5-iumiodide (from step 5, 0.22 g) in dry dichloromethane (4.5 mL) at −40° C.was added anisole (0.36 mL, 3.34 mmol) followed by 2M AlCl₃ in CH₃NO₂(1.7 mL, 3.52 mmol). The liquid was stirred at 0° C. for 30 min. To thereaction mixture were added di-isopropyl ether (5 mL) and water (0.5mL), and the resultant mixture was stirred to generate a precipitate.The supernatant was removed by decantation. To the insoluble matteradhering to the vessel were added dilute aqueous hydrochloric acidsolution (2 mL) and acetonitrile (5 mL) and was stirred to dissolve thematter completely. Thereto was added HP20 resin (0.5 g), stirred for 30min. and then filtered. The filtrate was concentrated and freeze-driedto give a crude product, which was purified by HPLC to obtain(6R,7R)-7-{[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-{[1-(4-carbamimidoylbenzyl)-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylateas formic acid salt (0.02 g, 15.5%).

¹H NMR (D₂O): δ 1.25 (s, 6H), 2.94 (d, 1H, J=17.6 Hz), 3.38 (d, 1H,J=18.0 Hz), 5.08-5.13 (m, 2H), 5.33 (d, 1H, J=14.4 Hz), 5.53 (s, 2H),5.63 (d, 1H, J=4.8 Hz), 6.76 (s, 1H), 6.94 (s, 1H), 7.22 (d, 2H, J=7.2Hz), 7.55 (d, 2H, J=7.6 Hz), 7.68 (m, 2H), 8.23 (d, 1H, J=7.2 Hz), 9.06(s, 1H). Seven protons were not observed in D₂O.

Example 2 (Table 1, Compound 9)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-{[1-(4-carbamimidoylbenzyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

Step 1:4-((2,3-Dihydro-1H-imidazo[1,2-b]pyrazol-1-yl)methyl)benzonitrile

To a solution of 2,3-dihydro-1H-imidazo[1,2-b]pyrazole (1.399 g, 12.84)in dimethyl formamide (10 mL) was added 4-(bromomethyl)benzonitrile(2.86 g, 12.84 mmol) followed by potassium carbonate (2.66 g, 19.26mmol) and the reaction mixture was stirred under nitrogen 20 h, thendiluted with ethyl acetate (100 mL) and water (100 mL). The organiclayer was separated, washed with water (3×100 mL) followed by brinesolution (200 mL), dried over Na₂SO₄ and concentrated under reducedpressure. Purification of the crude product by silica gel columnchromatography using ethyl acetate as eluent gave4-((2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-yl)methyl)benzonitrile (2.1g, 72.9%) as a solid.

¹H NMR (400 MHz, DMSO-d₆): δ 3.66 (t, 2H), 4.07 (t, 2H), 4.31 (s, 2H),5.22 (d, 2H, J=2.0 Hz), 7.19 (d, 1H, J=1.5 Hz), 7.58 (d, 2H, J=8.2 Hz),7.85 (d, 2H, J=8.2 Hz)

Step 2: Ethyl4-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-ylmethyl)benzenecarboximidatehydrochloride

Through a solution of4-((2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-yl)methyl)benzonitrile (fromstep 1, 1.5 g, 6.69 mmol) in anhydrous methanol in a pressure vessel at0° C. was bubbled a stream of anhydrous hydrogen chloride gas for 15min. The reaction vessel was stoppered and stirred at room temperaturefor 20 h, the contents were transferred to a flask and evaporated invacuo. The crude product was triturated with ether and dried undervacuum to get ethyl4-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-ylmethyl)benzenecarboximidatehydrochloride (1.8 g, 87.8%) as a solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.49 (t, 3H), 3.77 (dd, 2H, J=4.2 Hz), 4.17(t, 2H), 4.43 (dd, 2H, 10.0 Hz), 4.63 (q, 2H, J=7.1 Hz), 5.51 (d, 1H,J=2.3 Hz), 6.00 (br s, 2H), 7.63 (d, 2H, J=8.0 Hz), 8.14 (d, 2H, J=8.0Hz), 12.20 (br s, 2H).

Step 3:4-(2,3-Dihydro-1H-imidazo[1,2-b]pyrazol-1-ylmethyl)benzenecarboximidamide

A pressure vessel containing a suspension of ethyl4-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-ylmethyl)benzenecarboximidatehydrochloride (from step 2, 1.8 g, 5.87 mol) in methanol (25 mL) wassaturated with ammonia gas and stoppered. The reaction mixture wasstirred at room temperature for 24 h, then the excess ammonia was ventedout and the contents were concentrated under reduced pressure. Theresidue was triturated with hexanes and dried under vacuum to give4-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-ylmethyl)benzenecarboximidamide(0.95 g, 66.9%) as a solid.

¹H NMR (400 MHz, DMSO-d₆): δ 3.66 (t, 2H), 4.06 (t, 2H), 4.31 (t, 2H),5.22 (d, 1H, J=2.0 Hz), 7.17 (d, 1H, J=1.6 Hz), 7.71 (d, 2H, J=8.2 Hz),7.83 (d, 2H, J=8.2 Hz)

Mass: ES⁺ 242.10

Step 4: tert-Butyl{[4-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-ylmethyl)phenyl]carbonoimidoyl}carbamate

To a suspension of4-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-ylmethyl)benzenecarboximidamide(from step 3, 0.95 g, 3.94 mmol) in a mixture of sodium bicarbonate(1.60 g, 19.7 mmol), 1,4-dioxane (25 mL) and water (10 mL) was addeddi-tert-butyl dicarbonate (2.74 g, 12.54 mmol) and stirred at roomtemperature for 24 h. The reaction mixture was concentrated underreduced pressure to remove the volatiles and the remaining solution wasdissolved in ethyl acetate (80 mL), washed with water (80 mL), brinesolution (80 mL), dried and concentrated. The crude product was purifiedby silica gel column chromatography using ethyl acetate as eluent toafford tert-butyl{[4-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-ylmethyl)phenyl]carbonoimidoyl)}carbamate(0.45 g, 33.5%).

¹H NMR (400 MHz, DMSO-d₆): δ 1.42 (s, 9H), 3.63 (t, 2H), 4.24 (t, 2H),5.18 (d, 1H, J=2.0 Hz), 7.16 (d, 1H, J=2.0 Hz), 7.45 (d, 2H, J=8.0 Hz),7.92 (d, 2H, J=8.0 Hz).

Step 5:5-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-Butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-{[(1-tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy]imino}acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-{4-[N-(tert-butoxycarbonyl)carbamimidoyl]benzyl}-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-5-iumiodide

To a solution of 4-methoxybenzyl(6R,7R)-7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate(0.35 g, 0.449 mmol) in dimethylformamide (8 mL) at room temperature wasadded potassium iodide (0.149 g, 0.898 mmol) and after stirring for 10min was added tert-butyl{[4-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-1-ylmethyl)phenyl]carbonoimidoyl}carbamate(from step 4, 153 mg, 0.449 mmol). The reaction mixture was then stirredunder nitrogen at room temperature for 16 h and diluted with a 1:1mixture of sodium thio sulfate and brine (15 mL) solution. Thesuspension was then filtered, washed with water and the solid was vacuumdried to get a yellow solid (0.448 g), which was used in the next stepwithout further purification.

Step 6:(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-{[1-(4-carbamimidoylbenzyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

To a solution of5-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-{[(1-tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy]imino}acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-{4-[N-(tert-butoxycarbonyl)carbamimidoyl]benzyl}-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-5-iumiodide (from step 5, 0.45 g) in dry dichloromethane (15 mL) undernitrogen at room temperature was added anisole (0.8 mL) followed bytrifluoroacetic acid (3 mL) in one portion and stirred for 3 h. Thereaction mixture was concentrated under reduced pressure and the residuewas suspended in distilled water (20 mL), stirred for 20 min andfiltered. The filtrate was lyophilized and the product was purified byHPLC to obtain(6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-{[1-(4-carbamimidoylbenzyl)-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylateas a formic acid salt (0.022 g, 8.4%).

¹H NMR (400 MHz, D₂O): δ 1.33 (s, 6H), 3.08 (d, 1H, J=18.0 Hz), 3.31 (d,1H, J=18.0 Hz), 3.86 (t, 2H), 4.12 (q, 1H, J=8.6 Hz), 4.22 (q, 1H, J=8.2Hz), 4.44 (q, 2H, J=3.5 Hz), 4.85 (dd, 2H, J=15.6 and 19.7 Hz), 5.07 (d,1H), 5.64 (d, 1H), 5.66 (d, 1H), 6.87 (s, 1H), 7.42 (d, 2H), 7.63 (d,2H), 7.81 (1H, d), 8.17 (1H, s).

Mass: ES⁺ 709.19

Example 3 (Table 1, Compound 2)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]-amino}-8-oxo-3-{[1-(4-{N-[(3R)-piperidin-3-yl]carbamimidoyl}benzyl)-1H-pyrazol[4,3-c]pyridin-5-ium-5-yl]methyl}-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

Step 1: 4-(1H-Pyrazolo[4,3-c]pyridin-1-ylmethyl)benzonitrile

A mixture of 1H-pyrazolo[4,3-c]pyridine (0.72 g, 6.04 mmol),4-(bromomethyl)benzonitrile (1.57 g, 8.01 mmol) and potassium carbonate(1.67 g, 12.08 mmol) in DMF (75 mL) was stirred at 60° C. for 24 h andconcentrated. The residue was partitioned between ethyl acetate (100 mL)and water (100 mL). The organic layer was separated, washed with brine(3×100 mL), dried (Na₂SO₄) and concentrated. The crude product waspurified by silica gel column chromatography using ethyl acetate:methanol (9:1) as eluent to afford4-(1H-pyrazolo[4,3-c]pyridin-1-ylmethyl)benzonitrile (0.42 g, 30.5%) asa solid.

¹H NMR (400 MHz, CDCl₃): δ 5.66 (s, 2H), 7.24-7.28 (m, 3H), 7.61 (d, 2H,J=8.4 Hz), 8.23 (s, 1H), 8.43 (d, 1H, J=6.4 Hz), 9.15 (s, 1H).

Step 2: Ethyl4-(1H-pyrazolo[4,3-c]pyridin-1-ylmethyl)benzenecarboximidatehydrochloride

Through a solution of4-(1H-pyrazolo[4,3-c]pyridin-1-ylmethyl)benzonitrile (from step 1, 0.7g, 3.0 mmol) in anhydrous ethanol (30 mL) in a pressure vessel at 0° C.was bubbled a stream of anhydrous hydrogen chloride gas for 10 min. Thereaction vessel was stoppered, then stirred at room temperature for 18 hand the contents were transferred into a flask and evaporated underreduced pressure. The crude product was triturated with ether and driedunder vacuum to provide ethyl4-(1H-pyrazolo[4,3-c]pyridin-1-ylmethyl)benzenecarboximidatehydrochloride (0.8 g, 84%) as a solid.

¹H NMR (400 MHz, CD₃OD): δ 1.59 (t, 3H, J=6.6 Hz), 4.63 (q, 2H, J=6.2Hz), 6.03 (s, 2H), 7.60 (d, 2H, J=6.8 Hz), 8.04 (d, 2H, J=7.2 Hz), 8.37(s, 1H), 8.58 (s, 1H), 8.84 (s, 1H), 9.59 (s, 1H). One proton was notobserved in CD₃OD.

Step 3: tert-Butyl(3R)-3-({[4-(1H-pyrazolo[4,3-c]pyridin-1-ylmethyl)phenyl]carbonoimidoyl}amino)piperidine-1-carboxylate

To a solution of ethyl4-(1H-pyrazolo[4,3-c]pyridin-1-ylmethyl)benzenecarboximidatehydrochloride (from step 2, 0.57 g, 1.8 mmol) and triethylamine (0.56mL, 4.0 mmol) in methanol (5 mL) was added tert-butyl(3R)-3-aminopiperidine-1-carboxylate (0.36 g, 1.8 mmol) in methanol (1mL) at 0° C. The reaction mixture was stirred at room temperature for 2days and concentrated. The residue was purified by column chromatographyusing methanol: ethyl acetate (1:4) as eluent to give tert-butyl(3R)-3-({[4-(1H-pyrazolo[4,3-c]pyridin-1ylmethyl)phenyl]carbonoimidoyl}amino)piperidine-1-carboxylate (0.5 g,64%) as a solid.

¹H NMR (400 MHz, CDCl₃): δ 1.28 (s, 9H), 1.57-1.80 (m, 3H), 2.12 (s,1H), 3.08-3.30 (m, 2H), 3.36-4.10 (m, 3H), 5.83 (s, 2H), 7.45 (d, 2H,J=8.8 Hz), 7.67-7.69 (m, 3H), 8.33 (d, 1H, J=6.0 Hz), 8.37 (s, 1H), 9.10(s, 1H). Two protons were not observed in CD₃OD.

Step 4: tert-Butyl(3R)-3-[(tert-butoxycarbonyl){[4-(1H-pyrazolo[4,3-c]pyridin-1-ylmethyl)phenyl]carbonoimidoyl}amino]piperidine-1-carboxylate

A solution of tert-butyl(3R)-3-({[4-(1H-pyrazolo[4,3-c]pyridin-1ylmethyl)phenyl]carbonoimidoyl}amino)piperidine-1-carboxylate(from step 3, 0.5 g. 1.15 mmol) in 1,4-dioxane (20 mL) was treated witha saturated sodium carbonate solution (10 mL) followed by di-tert-butyldicarbonate (1.26 g, 5.78 mmol), then stirred at room temperature for 40h. The reaction mixture was concentrated under reduced pressure toremove the volatiles and the remaining solution was dissolved in ethylacetate (100 mL) and washed with water (100 mL), brine solution (100mL), dried, and concentrated. The crude product was purified by silicagel column chromatography using ethyl acetate: methanol: ammoniumhydroxide (60:39:1) as eluent to afford tert-butyl(3R)-3-[(tert-butoxycarbonyl){[4-(1H-pyrazolo[4,3-c]pyridin-1-ylmethyl)phenyl]carbonoimidoyl}amino]piperidine-1-carboxylate(0.48 g, 78%).

¹H NMR (400 MHz, CDCl₃): δ 1.24-2.05 (m, 22H), 3.05-3.71 (m, 4H),4.09-4.10 (m, 1H), 5.08 (br s, 1H), 5.62 (s, 2H), 7.22-7.28 (m, 3H),7.39 (d, 2H, J=8.4 Hz), 8.19 (s, 1H), 8.38 (d, 1H, J=6.0 Hz), 9.12 (s,1H).

Step 5:5-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-Butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-{[(1-tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy]imino}acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-(4-{N-(tert-butoxycarbonyl)-N-[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl]carbamimidoyl}benzyl)-1H-pyrazolo[4,3-c]pyridin-5-iumiodide

To a solution of tert-butyl(3R)-3-[(tert-butoxycarbonyl){[4-(1H-pyrazolo[4,3-c]pyridin-1-ylmethyl)phenyl]carbonoimidoyl}amino]piperidine-1-carboxylate(from step 4, 0.16 g, 0.30 mmol) in dimethylacetamide (2 mL) was added4-methoxybenzyl(6R,7R)-7-{[(2Z)-2-{5-[(tert-butoxycarbonyl)amino]-1,2,4-thiadiazol-3-yl}-2-{[(1-tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy]imino}acetyl]amino}-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate(0.23 g, 0.30 mmol) at 0° C. The reaction mixture was then degassedunder reduced pressure for 0.5 h, and thereto was added sodium iodide(0.09 g, 0.60 mmol). After stirring at 15° C. for 16 h, the reactionmixture was slowly added to 5% aqueous sodium chloride and sodiumthiosulfate solution cooled under ice. The suspension was then filtered,washed with water and the solid was vacuum dried to get a yellow solid(0.33 g) which was used in the next step without further purification.

Step 6:(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-8-oxo-3-{[1-(4-{N-[(3R)-piperidin-3-yl]carbamimidoyl}benzyl)-1H-pyrazolo[4,3-c]pyridin-5-ium-5-yl]methyl}-5-thia-1-azabicyclo[4.2.1]oct-2-ene-2-carboxylate

To a solution of5-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-{[(1-tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy]imino}acetyl]amino}-2-[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-(4-{N-(tert-butoxycarbonyl)-N-[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl]carbamimidoyl}benzyl)-1H-pyrazolo[4,3-c]pyridin-5-iumiodide (from step 5, 0.33 g) in dry dichloromethane (6 mL) at −40° C.was added anisole (0.50 mL, 4.64 mmol) and then 2M aluminium chloride innitromethane (2.33 mL, 4.66 mmol). The liquid was stirred at 0° C. for30 min. To the reaction mixture were added di-isopropyl ether (10 mL)and water (0.8 mL), and the resultant was stirred to generate aprecipitate. The supernatant was removed by decantation. To theinsoluble matter adhering to the vessel were added dilute aqueoushydrochloric acid solution (4 mL) and acetonitrile (15 mL). Theresultant was stirred to dissolve the matter completely. Thereto wasadded HP20 resin (0.8 g), and stirred for 30 min, and then filtered. Thefiltrate was concentrated and freeze-dried to give a crude product whichwas purified by HPLC to obtain(6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-8-oxo-3-{[1-(4-{N-[(3R)-piperidin-3-yl]carbamimidoyl}benzyl)-1H-pyrazolo[4,3-c]pyridin-5-ium-5-yl]methyl}-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylateas a formic acid salt (0.025 g, 12.5%).

¹H NMR (400 MHz, D₂O): δ 1.17 (s, 6H), 1.58-1.70 (m, 2H), 1.88-1.92 (m,1H), 2.08-2.09 (m, 1H), 2.85-2.98 (m, 3H), 3.20 (d, 1H, J=12.0 Hz),3.45-3.49 (m, 2H), 3.96 (m, 1H), 5.08-5.11 (m, 2H), 5.43 (d, 1H, J=14.8Hz), 5.58 (d, 1H, J=4.4 Hz), 5.72 (s, 2H), 6.65 (s, 1H), 7.26 (d, 2H,J=8.0 Hz), 7.50 (d, 2H, J=7.2 Hz), 7.90 (d, 1H, J=6.8 Hz), 8.50 (d, 1H,J=7.2 Hz), 8.58 (s, 1H), 9.49 (s, 1H). Seven protons were not observedin D₂O.

Mass: ES⁺ 802.20

Example 4 (Table 1, Compound 5)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-{[1-(4-carbamimidoylbenzyl)-1H-imidazo[1,2-b]pyrazol-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

Step 1: 4-(1H-Imidazo[1,2-b]pyrazol-1-ylmethyl)benzonitrile

To a solution of 1H-imidazo[1,2-b]pyrazole (2.158 g, 20.146 mmol) in DMF(30 mL) under nitrogen at 0° C. was added sodium hydride (60.9% inmineral oil, 1.19 g, 30.22 mmol) in portions and after stirring for 15min was added 4-(bromomethyl)benzonitrile (3.95 g, 20.146 mmol) inportions. The reaction mixture was stirred at 0° C. for 2 h then at roomtemperature for 1 h and quenched with saturated ammonium chloridesolution, then diluted with ethyl acetate (200 mL) and water (200 mL).The organic layer was separated, washed with water (3×200 mL), brinesolution, dried (Na₂SO₄) and concentrated. The crude product waspurified by silica gel column chromatography using ethyl acetate toafford 4-(1H-imidazo[1,2-b]pyrazol-1-ylmethyl)benzonitrile (2.2 g, 49%)as a solid.

¹H NMR (400 MHz, DMSO-d₆): δ 5.25 (s, 2H), 5.62 (d, 1H, J=2.7 Hz),7.34-7.35 (m, 1H), 7.44-7.47 (m, 3H), 7.59-7.60 (m, 1H), 7.84 (d, 2H,J=8.2 Hz).

Step 2: Ethyl4-(1H-imidazo[1,2-b]pyrazol-1-ylmethyl)benzenecarboximidatehydrochloride

Through a solution of4-(1H-imidazo[1,2-b]pyrazol-1-ylmethyl)benzonitrile (from step 1, 1.2 g,5.4 mmol) in anhydrous ethanol (25 mL) in a pressure vessel at 0° C. wasbubbled a stream of anhydrous hydrogen chloride gas for 15 min. Thereaction vessel was stoppered and stirred at room temperature for 18 h,then the contents were transferred into a flask and evaporated underreduced pressure. The crude product was triturated with ether and driedunder vacuum to provide ethyl4-(1H-imidazo[1,2-b]pyrazol-1-ylmethyl)benzenecarboximidatehydrochloride (1.6 g, 97%) as a solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.46 (t, 3H, J=7.1 Hz), 4.73 (q, 2H, J=6.9Hz), 5.41 (s, 2H), 5.98 (d, 1H, J=2.8 Hz), 7.56-7.61 (m, 4H), 7.80 (d,2H, J=8.6 Hz), 8.14 (d, 2H, J=8.6 Hz), 12.20 (br s, 2H).

Step 3: 4-(1H-Imidazo[1,2-b]pyrazol-1-ylmethyl)benzenecarboximidamide

A pressure vessel containing a suspension of ethyl4-(1H-imidazo[1,2-b]pyrazol-1-ylmethyl)benzenecarboximidatehydrochloride (from step 2, 1.1 g, 3.61 mol) in methanol (25 mL) wassaturated with ammonia gas and stoppered. The reaction mixture wasstirred at room temperature for 24 h, then excess ammonia was vented outand the contents were concentrated under reduced pressure. The residuewas triturated with hexanes and dried under vacuum to give4-(1H-imidazo[1,2-b]pyrazol-1-ylmethyl)benzenecarboximidamide (1.5 g,141.5%) as a solid.

¹H NMR (400 MHz, DMSO-d₆): δ 5.27 (s, 2H), 5.64 (d, 1H, J=2.4 Hz),7.35-7.60 (m, 5H), 7.80-7.86 (m, 2H)

Step 4: tert-Butyl{[4-(1H-imidazo[1,2-b]pyrazol-1-ylmethyl)phenyl]carbonoimidoyl}carbamate

To a suspension of4-(1H-imidazo[1,2-b]pyrazol-1-ylmethyl)benzenecarboximidamide (from step3, 1.50 g. 6.27 mmol) in a mixture of sodium bicarbonate (1.524 g, 18.81mmol), 1,4-dioxane (30 mL) and water (10 mL) was added di-tert-butyldicarbonate (2.74 g, 12.54 mmol) and stirred at room temperature for 20h. The reaction mixture was concentrated under reduced pressure toremove the volatiles and the remaining solution was dissolved in ethylacetate (80 mL), washed with water (80 mL), brine solution (80 mL),dried and concentrated. The crude product was purified by silica gelcolumn chromatography using ethyl acetate as eluent to afford tert-butyl{[4-(1H-imidazo[1,2-b]pyrazol-1-ylmethyl)phenyl]carbonoimidoyl}carbamate(0.60 g, 28.17%).

¹H NMR (400 MHz, DMSO-d₆): δ 1.41 (s, 9H), 5.18 (s, 2H), 5.58 (d, 1H,J=2.3 Hz), 7.32-7.37 (m, 3H), 7.41-7.42 (m, 1H), 7.56 (d, 1H, J=2.8 Hz),7.88 (d, 2H, J=8.5 Hz).

Mass: ES⁻ 338.11

Step 5:5-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-Butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-{[(1-tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy]imino}acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-{4-[N-(tert-butoxycarbonyl)carbamimidoyl]benzyl}-1H-imidazo[1,2-b]pyrazol-5-iumiodide

To a solution of 4-methoxybenzyl(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-{[(1-tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy]imino}acetyl]amino}-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate(0.35 g, 0.449 mmol) in dimethylformamide (8 mL) at room temperature wasadded potassium iodide (0.149 g, 0.898 mmol) and after stirring for 10min was added tert-butyl{[4-(1H-imidazo[1,2-b]pyrazol-1-ylmethyl)phenyl]carbonoimidoyl}carbamate(from step 4, 152 mg, 0.449 mmol). The reaction mixture was then stirredunder nitrogen at room temperature for 16 h and diluted with a 1:1mixture of sodium thio sulfate and brine solution (15 mL). Thesuspension was then filtered, washed with water and the solid was vacuumdried to get a yellow solid (0.650 g), which was used in the next stepwithout further purification.

Step 6:(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-{[1-(4-carbamimidoylbenzyl)-1H-imidazo[1,2-b]pyrazol-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

To a solution of5-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-{[(1-tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy]imino}acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-{4-[N-(tert-butoxycarbonyl)carbamimidoyl]benzyl}-1H-imidazo[1,2-b]pyrazol-5-iumiodide (from step 5, 0.65 g) in dry dichloromethane under nitrogen atroom temperature was added trifluoroacetic acid (5 mL) in one portionand stirred for 3 h. The reaction mixture was concentrated under reducedpressure and the residue was suspended in distilled water (20 mL),stirred for 20 min then filtered. The filtrate was lyophilized and theproduct was purified by HPLC to obtain(6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-{[1-(4-carbamimidoylbenzyl)-1H-imidazo[1,2-b]pyrazol-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylateas formic acid salt (0.032 g, 7.9%).

¹H NMR (400 MHz, DMSO-d₆): δ 1.29 (d, 6H, J=8.2 Hz), 2.94 (d, 1H, J=18.0Hz), 3.25 (d, 1H, J=18 Hz), 5.05 (d, 1H, J=5.0 Hz), 5.14 (s, 2H), 5.32(s, 2H), 5.63 (d, 1H, J=4.7 Hz), 6.13 (d, 1H, J=3.5 Hz), 6.86 (s, 1H),7.37-7.41 (m, 3H), 7.63 (d, 2H, J=8.6 Hz), 7.87 (d, 2H, J=3.2 Hz), 8.16(s, 1H)

Mass: ES⁺ 707.17

Example 5 (Table 1, Compound 11)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-({1-[(4-carbamimidoylthiophen-2-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

Step 1: (4-Bromothiophen-2-yl)methanol

Sodium borohydride (2.08 g, 55.0 mmol) was added to a solution of4-bromothiophene-2-carbaldehyde (10.0 g, 52.3 mmol) in anhydroustetrahydrofuran (200 mL) at room temperature and the resulting reactionmixture was stirred at room temperature for 1.5 h. Then the reactionmixture was quenched carefully by adding saturated aq. ammonium chloridesolution (50 mL). The reaction mixture was extracted with ethyl acetate(200 mL). Organic phase was separated, dried over Na₂SO₄. Solvent wasevaporated, crude compound was dried under vacuum to give(4-bromothiophen-2-yl) methanol (10.56 g, crude) as white semi-solidwhich was used in the next step without further purification.

¹H NMR (400 MHz, CDCl₃): δ 4.79 (s, 2H), 6.92 (s, 1H), 7.17 (s, 1H).

Step 2: 5-(Hydroxymethyl)thiophene-3-carbonitrile

A mixture of (4-bromothiophen-2-yl) methanol (from step 1, 10.56 gcrude, -52.3 mmol), zinc cyanide (6.14 g, 52.34 mmol) in a 500 mL roundbottom flask was degassed three times with nitrogen. Then anhydrousdimethylformamide (75 mL) was added, and the mixture was degassed withnitrogen. After that was added Palladium-tetrakis(triphenylphosphine)(3.01 g, 2.61 mmol) and degassing was repeated once again. The flask wasfitted with a reflux condenser, and the reaction mixture was stirred at80° C. (bath temperature) for 4 h under nitrogen. The mixture was cooledto room temperature, solvent was evaporated. The crude compound waspurified by flash chromatography using RediSep silica 120 g flash column(10-30% ethyl acetate in hexanes as eluent) to give5-(hydroxymethyl)thiophene-3-carbonitrile (5.15 g, 71% over two steps)as white solid.

¹H NMR (400 MHz, CDCl₃): δ 2.26 (t, 1H, J=5.9 Hz), 4.84 (d, 2H, J=5.9Hz), 7.16 (s, 1H), 7.88 (d, 1H, J=1.6 Hz).

Step 3: 5-(Bromomethyl)thiophene-3-carbonitrile

A solution of 5-(hydroxymethyl)thiophene-3-carbonitrile (from step 2,5.15 g, 37.0 mmol) in anhydrous tetrahydrofuran (150 mL) was addedtriphenyl phosphine (10.19 g, 38.8 mmol) followed by carbon tetrabromide(12.88 g, 38.8 mmol). The reaction mixture was stirred at roomtemperature for 20 h under nitrogen. Solvent was evaporated and thecrude compound was purified by flash chromatography using RediSep silica120 g flash column (0-10% ethyl acetate in hexanes as eluent) to give5-(bromomethyl)thiophene-3-carbonitrile (6.07 g, 81%) as a white solid.

¹H NMR (400 MHz, CDCl₃): δ 4.66 (s, 2H), 7.28 (d, 1H, J=0.8 Hz), 7.92(d, 1H, J=1.6 Hz).

Step 4: 5-(1H-Pyrrolo[3,2-c]pyridin-1-ylmethyl)thiophene-3-carbonitrile

To a solution of 1H-pyrrolo[3,2-c]pyridine (1.77 g, 15.00 mmol) inanhydrous dimethylformamide (75 mL) was added sodium hydride (60%suspension in mineral oil, 0.75 g, 18.75 mmol) at 0° C. in smallportions under nitrogen. After the addition, reaction mixture wasstirred for 15 minutes at 0° C. and then at room temperature for 10minutes. Cooled to 0° C., 5-(bromomethyl)thiophene-3-carbonitrile (fromstep 3, 3.79 g, 18.75 mmol) was added in small portions. After theaddition, reaction mixture was stirred for 10 minutes at 0° C. and thenat room temperature for 1 h. Quenched with water (10 mL), solvent wasevaporated under reduced pressure. Residue was partitioned between ethylacetate (150 mL) and water (100 mL). Organic phase was separated, washedwith brine and dried over Na₂SO₄. The crude compound was purified byflash chromatography using RediSep silica 80 g flash column (0-3%methanol in methylene chloride as eluent) to give5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)thiophene-3-carbonitrile (2.17 g,60%) as a brown solid.

¹H NMR (400 MHz, CDCl₃): δ 5.47 (s, 2H), 6.68 (d, 1H, J=3.1 Hz), 7.10(s, 1H), 7.15 (d, 1H, J=3.5 Hz), 7.23 (d, 1H, J=5.8 Hz), 7.83 (s, 1H),8.35 (d, 1H, J=5.9 Hz).

Mass: ES⁺ 240.01

Step 5: Methyl5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)thiophene-3-carboximidatehydrochloride

Anhydrous hydrogen chloride gas was bubbled through a solution of5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)thiophene-3-carbonitrile (fromstep 4, 1.05 g, 4.38 mmol) in anhydrous methanol (30 mL) at roomtemperature for 45 minutes. The reaction mixture was stirred at roomtemperature for 20 h. Solvent was evaporated and dried under vacuum togive methyl5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)thiophene-3-carboximidatehydrochloride (1.05 g crude) as brown color gummy solid which was usedin next step without further purification.

Mass: ES⁺ 272.06.

Step 6:5-(1H-Pyrrolo[3,2-c]pyridin-1-ylmethyl)thiophene-3-carboximidamide

Anhydrous ammonia gas was bubbled through a solution of methyl5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)thiophene-3-carboximidatehydrochloride (from step 5, 1.05 g crude, −4.3 mmol) in anhydrousmethanol (20 mL) at room temperature for 45 minutes. The reactionmixture was stirred at room temperature for 16 h. Solvent was evaporatedand dried under vacuum to give5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)thiophene-3-carboximidamide (1.72g crude) as a brown solid which was used in the next step withoutfurther purification.

¹H NMR (400 MHz, DMSO-d₆): δ 5.90 (br s, 2H), 7.00 (br s, 1H), 7.42 (brs, 2H), 7.85 (s, 1H), 8.00 (br s, 1H), 8.19 (br s, 1H), 8.43 (br s, 1H),8.65 (s, 1H), 9.19 (br s, 1H), 9.52 (br s, 1H).

Mass: ES⁺ 257.05.

Step 7: tert-Butyl{[5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)thiophen-3-yl]carbonoimidoyl}carbamate

To a solution of5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)thiophene-3-carboximidamide (fromstep 6, 1.72 g crude, ˜4.0 mmol) in 1,4-dioxane (50 mL) was addedaqueous saturated sodium bicarbonate solution followed bydi-tert-butyldicarbonate (3.50 g, 16.0 mmol). The reaction mixture wasstirred at room temperature for 4 h. Solvent was evaporated, water (50mL) was added and extracted with methylene chloride (2×50 mL). Theorganic phase was dried over Na₂SO₄. Solvent was evaporated and thecrude compound was purified by flash chromatography using RediSep silica40 g flash column (0-2% methanol in methylene chloride as eluent) togive tert-butyl{[5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)thiophen-3-yl]carbonoimidoyl}carbamate(0.17 g, 11% for three steps) as an off-white solid.

¹H NMR (400 MHz, CDCl₃): δ 1.53 (s, 9H), 5.42 (s, 2H), 6.64 (d, 1H,J=2.7 Hz), 7.15 (d, 1H, J=3.5 Hz), 7.23 (d, 1H, J=5.5 Hz), 7.41 (s, 1H),7.86 (s, 1H), 8.28 (d, 1H, J=5.9 Hz), 8.89 (s, 1H).

Mass: ES⁺ 355.10.

Step 8:5-{[(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[((1-tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy]imino}acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-({4-[N-(tert-butoxycarbonyl)carbamimidoyl]thiophen-2-yl}methyl)-1H-pyrrolo[3,2-c]pyridin-5-iumiodide

A mixture of tert-butyl{[5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)thiophen-3-yl]carbonoimidoyl}carbamate(from step 7, 107 mg, 0.30 mmol), 4-methoxybenzyl(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-{[(1-tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy]imino}acetyl]amino}-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate(234 mg, 0.30 mmol), and sodium iodide (90 mg, 0.60 mmol) was cooled to0° C. in an ice-bath; dimethyl formamide (3 mL) was added, stirred for45 minutes, then the mixture was stirred at −16° C. for 16 h undernitrogen. Sodium bisulphite (0.6 g) in sodium chloride solution (75 mL)was added at 15° C., stirred for 10 minutes. The solid separated wasfiltered off, washed with water and dried under vacuum to give5-(((6R,7R)-7-((Z)-2-(2-aminothiazol-4-yl)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)acetamido)-2-(((4-methoxybenzyl)oxy)carbonyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl)-1-((4-(N-(tert-butoxycarbonyl)carbamimidoyl)thiophen-2-yl)methyl)-1H-pyrrolo[3,2-c]pyridin-5-iumiodide (296 mg, crude) as yellow color solid which was used in the nextstep without further purification.

Mass: ES⁺ 1100.52.

Step 9:(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-({1-[(4-carbamimidoylthiophen-2-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

To a solution of5-{[(6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(1-tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy]imino}acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-({4-[N-(tert-butoxycarbonyl)carbamimidoyl]thiophen-2-yl}methyl)-1H-pyrrolo[3,2-c]pyridin-5-iumiodide (from step 8, 296 mg, crude, −0.30 mmol)) in anhydrous methylenechloride (3 mL) was added anisole (0.8 mL) followed by trifluoroaceticacid (2.0 mL). The reaction mixture was stirred at room temperature for3 h. 55 Solvent was evaporated and diisopropyl ether (30 mL) was added.The solid separated was filtered, washed with diisopropyl ether anddried under vacuum. The light brown color solid (356 mg) was dissolvedin water (20 mL) and filtered. The aqueous phase was lyophilized to giveyellow solid (200 mg) which was purified by preparative HPLC(acetonitrile, water, 0.1% formic acid) to give(6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-({1-[(4-carbamimidoylthiophen-2-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylateas a formic acid salt (30 mg, 14%).

¹H NMR (400 MHz, D₂O): δ 1.24 (s, 3H), 1.26 (s, 3H), 2.94 (d, 1H, J=18.0Hz), 3.42 (d, 1H, J=18.0 Hz), 5.01-5.14 (m, 2H), 5.39 (d, 1H, J=14.5Hz), 5.59-5.76 (m, 3H), 6.75 (s, 1H), 6.95 (d, 1H, J=3.5 Hz), 7.31 (s,1H), 7.73 (d, 1H, J=3.5 Hz), 7.88 (d, 1H, J=7.0), 8.09 (d, 1H, J=1.6Hz), 8.37 (d, 1H, J=7.0 Hz), 9.10 (s, 1H).

Mass: ES⁺ 724.17.

Example 6 (Table 1, Compound 13)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-({1-[(4-carbamimidoylfuran-2-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

Step 1: (4-Bromofuran-2-yl)methanol

Sodium borohydride (1.21 g, 31.98 mmol) was added to a solution of4-bromofuran-2-carbaldehyde (5.33 g, 30.46 mmol) in anhydroustetrahydrofuran (120 mL) at room temperature and the resulting reactionmixture was stirred at room temperature for 1.5 h. Then the reactionmixture was quenched carefully by adding saturated aqueous ammoniumchloride solution (50 mL) and extracted with ethyl acetate (200 mL). Theorganic phase was separated and dried over Na₂SO₄. Solvent wasevaporated and the crude compound was dried under vacuum to give(4-bromofuran-2-yl) methanol (5.34 g) as white semi-solid, which wasused in the next step without further purification.

¹HNMR (400 MHz, CDCl₃): δ 2.36 (br s, 1H), 4.55 (s, 2H), 6.34 (s, 1H),7.39 (s, 1H).

Step 2: 5-(Hydroxymethyl)furan-3-carbonitrile

A mixture of (4-bromofuran-2-yl)methanol (from step 1, 3.50 g, 19.8mmol) and zinc cyanide (2.32 g, 19.8 mmol) in a 250 mL round bottomflask was degassed three times with nitrogen. Anhydrousdimethylformamide (20 mL) was added, and the mixture was degassed withnitrogen. After that Pd(PPh₃)₄ (1.38 g, 1.20 mmol) was added anddegassing was repeated once again. The flask was fitted with a refluxcondenser, and the reaction mixture was stirred at 80° C. for 24 h undernitrogen. The mixture was cooled to room temperature, solvent wasevaporated and residue was taken in ethyl acetate (150 mL), washed withwater (100 mL), brine (100 mL) and dried over Na₂SO₄. Solvent wasevaporated and the crude compound was purified by flash chromatographyusing RediSep silica 120 g flash column (0-30% ethyl acetate in hexanesas eluent) to give 5-(hydroxymethyl)furan-3-carbonitrile (0.58 g, 24%)as a white solid.

¹HNMR (400 MHz, CDCl₃): δ 1.97 (br s, 1H), 4.64 (d, 2H, J=6.3 Hz), 6.53(s, 1H), 7.92 (s, 1H).

Step 3: 5-(Bromomethyl)furan-3-carbonitrile

A solution of 5-(hydroxymethyl)furan-3-carbonitrile (from step 2, 0.92g, 7.47 mmol) in anhydrous tetrahydrofuran (30 mL) was added triphenylphosphine (2.15 g, 8.22 mmol) followed by carbon tetrabromide (2.72 g,8.22 mmol). The reaction mixture was stirred at room temperature for 4 hunder nitrogen. Solvent was evaporated and the crude compound waspurified by flash chromatography using RediSep silica 80 g flash column(10% ethyl acetate in hexanes as eluent) to give5-(bromomethyl)furan-3-carbonitrile (1.12 g, 81%) as a white solid.

¹H NMR (400 MHz, CDCl₃): δ 4.43 (s, 2H), 6.60 (s, 1H), 7.94 (s, 1H).

Step 4: 5-(1H-Pyrrolo[3,2-c]pyridin-1-ylmethyl)furan-3-carbonitrile

To a solution of 1H-pyrrolo[3,2-c]pyridine (0.77 g, 6.50 mmol) inanhydrous dimethylformamide (30 mL) was added sodium hydride (60%suspension in mineral oil, 0.26 g, 6.50 mmol) at 0° C. in small portionsunder nitrogen. After the addition, the reaction mixture was stirred for15 minutes at 0° C. and then at room temperature for 10 minutes thencooled to 0° C. and 5-(bromomethyl)furan-3-carbonitrile (from step 3,1.10 g, 5.91 mmol) was added in small portions. After the addition, thereaction mixture was stirred for 10 minutes at 0° C. then at roomtemperature for 1 h. The mixture was quenched with water (5 mL). Solventwas evaporated under reduced pressure. Residue was partitioned betweenethyl acetate (100 mL) and water (50 mL). The organic phase wasseparated, washed with brine and dried over Na₂SO₄. The crude compoundwas purified by flash chromatography using RediSep silica 40 g flashcolumn (0-3% methanol in methylene chloride as eluent) to give5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)furan-3-carbonitrile (1.065 g,80%) as an off-white solid.

¹HNMR (400 MHz, CDCl₃): δ 5.29 (s, 2H), 6.46 (s, 1H), 6.66 (d, 1H, J=2.3Hz), 7.15 (d, 1H, J=3.5 Hz), 7.27 (s, 1H), 7.88 (s, 1H), 8.37 (d, 1H,J=5.9 Hz), 8.94 (s, 1H).

Mass: ES⁺ 224.10.

Step 5: Methyl5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)furan-3-carboximidatehydrochloride

Anhydrous hydrogen chloride gas was bubbled through a solution of5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)furan-3-carbonitrile (from step4, 1.05 g, 4.70 mmol) in anhydrous methanol (30 mL) at room temperaturefor 45 minutes; the reaction mixture was stirred at room temperature for20 h. Solvent was evaporated and dried under vacuum to give methyl5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)furan-3-carboximidatehydrochloride (1.05 g, crude) as a brown gummy solid. The compound wasused in the next step without further purification. ¹H NMR (400 MHz,CD₃OD): δ 4.28 (s, 3H), 5.82 (s, 2H), 7.16 (br s, 1H), 7.22 (br s, 1H),7.98 (br s, 1H), 8.30 (br s, 1H), 8.46 (br s, 1H), 8.54 (s, 1H), 9.20(s, 1H).

Mass: ES⁺ 256.10.

Step 6: 5-(1H-Pyrrolo[3,2-c]pyridin-1-ylmethyl)furan-3-carboximidamide

Anhydrous ammonia gas was bubbled through a solution of methyl5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)furan-3-carboximidatehydrochloride (from step 5, 1.0 g crude, ˜4.7 mmol) in anhydrousmethanol (30 mL) at room temperature for 45 minutes. The reactionmixture was stirred at room temperature for 16 h. Solvent was evaporatedand dried under vacuum to give5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)furan-3-carboximidamide (1.90 g,crude) as a brown solid.

The compound was used in the next step without further purification.

Mass: ES⁺ 241.11.

Step 7: tert-Butyl{[5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)furan-3-yl]carbonoimidoyl}carbamate

To a solution of5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)furan-3-carboximidamide (fromstep 6, 1.90 g crude, ˜4.7 mmol) in 1,4-dioxane (5 mL) was added aqueoussaturated sodium bicarbonate solution (5 mL) followed bydi-tert-butyldicarbonate (4.10 g, 18.8 mmol) and the reaction mixturewas stirred at room temperature for 4 h. Solvent was evaporated, water(50 mL) was added and extracted with methylene chloride (2×50 mL). Theorganic phase was dried over Na₂SO₄. Solvent was evaporated and thecrude compound was purified by flash chromatography using RediSep silica40 g flash column (2-5% methanol in methylene chloride as eluent) togive tert-butyl{[5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)furan-3-yl]carbonoimidoyl}carbamate(116 mg, 7% over steps) as an off-white solid.

¹H NMR (400 MHz, CDCl₃): δ 1.51 (s, 9H), 5.26 (s, 2H), 6.59 (s, 1H),6.63 (dd, 1H, J=3.1, 0.8 Hz), 7.15 (d, 1H, J=3.5 Hz), 7.22 (d, 1H, J=5.9Hz), 8.01 (s, 1H), 8.22 (d, 1H, J=5.9 Hz), 8.85 (s, 1H).

Mass: ES⁺ 341.23.

Step 8:5-{[(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(1-tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy]imino}acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-({4-[N-(tert-butoxycarbonyl)carbamimidoyl]furan-2-yl}methyl)-1H-pyrrolo[3,2-c]pyridin-5-iumiodide

A mixture of tert-butyl{[5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)furan-3-yl]carbonoimidoyl}carbamate(from step 7, 110 mg, 0.32 mmol), 4-methoxybenzyl(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-{[(1-tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy]imino}acetyl]amino}-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate(252 mg, 0.32 mmol), and sodium iodide (96 mg, 0.64 mmol) was cooled to0° C. and dimethylformamide (3 mL) was added, stirred for 45 minutesthen the mixture was stirred at −16° C. for 16 h under nitrogen. Sodiumbisulphite (0.6 g) in sodium chloride solution (75 mL) was added at 15°C., stirred for 10 minutes, and the solid was filtered, washed withwater and dried under vacuum to give5-{[(6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(1-tert-butoxy-2-methyl-1-oxo-propan-2-yl)oxy]imino}acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-({4-[N-(tert-butoxycarbonyl)carbamimidoyl]furan-2-yl}methyl)-1H-pyrrolo[3,2-c]pyridin-5-iumiodide (328 mg, crude) as yellow solid which was used in the next stepwithout further purification.

Mass: ES⁺ 1084.68.

Step 9:(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-({1-[(4-carbamimidoylfuran-2-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

To a solution of5-{[(6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(1-tert-butoxy-2-methyl-1-oxopropan-2yl)oxy]imino}acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-({4-[N-(tert-butoxycarbonyl)carbamimidoyl]furan-2-yl}methyl)-1H-pyrrolo[3,2-c]pyridin-5-iumiodide (from step 8, 328 mg, crude, ˜0.32 mmol)) in anhydrous methylenechloride (3 mL) was added anisole (0.8 mL) followed by trifluoroaceticacid (2.0 mL). The reaction mixture was stirred at room temperature for3 h and the solvent was evaporated. To the residue was added diisopropylether (30 mL) and the solid separated was filtered off, washed withdiisopropyl ether and dried under vacuum to get greenish yellow colorsolid (315 mg), which was dissolved in water (30 mL) and filtered. Theaqueous phase was lyophilized to give yellow solid (160 mg), which waspurified by preparative HPLC to give(6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-({1-[(4-carbamimidoylfuran-2-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylateas formic acid salt (28 mg, 12% over two steps).

¹H NMR (400 MHz, D₂O): δ 1.27 (s, 3H), 1.28 (s, 3H), 2.97 (d, 1H, J=18.0Hz), 3.44 (d, 1H, J=18.0 Hz), 5.04-5.16 (m, 2H), 5.42 (d, 1H, J=14.5Hz), 5.66 (d, 1H, J=4.7 Hz), 6.72 (s, 1H), 6.84 (s, 1H), 6.96 (d, 1H,J=3.1 Hz), 7.74 (d, 1H, J=3.5 Hz), 7.96 (d, 1H, J=7.0 Hz), 8.14 (s, 1H),8.43 (d, 1H, J=7.0 Hz), 9.14 (s, 1H). Seven protons were not observed inD₂O.

Mass: ES⁺ 708.27.

Example 7 (Table 1, Compound 3)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-8-oxo-3-{[1-(4-{N-[(3R)-piperidin-3-yl]carbamimidoyl}benzyl)-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl]methyl}-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹HNMR (400 MHz, CD₃OD): δ 1.23 (s, 3H), 1.29 (s, 3H), 1.81-2.02 (m, 4H),2.89 (d, 1H, J=18.0 Hz), 2.99 (m, 1H), 3.16 (m, 1H), 3.40-3.51 (m, 2H),3.63 (d, 1H, J=17.6 Hz), 4.21 (m, 1H), 4.95 (m, 1H), 5.18 (d, 1H, J=4.8Hz), 5.66-5.83 (m, 3H), 5.93 (d, 1H, J=14.0 Hz), 6.78 (s, 1H), 7.14 (d,1H, J=3.2 Hz), 7.44 (d, 2H, J=8.0 Hz), 7.70 (d, 1H, J=6.8 H_(z)), 7.85(d, 1H, J=8.4 Hz), 8.07 (s, 1H), 8.34 (s, 1H), 9.29 (d, 1H, J=6.0 Hz),9.43 (s, 1H). Seven protons were not observed in CD₃OD.

Mass: ES⁻ 799.2.

Example 8 (Table 1, Compound 14)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-{[1-(4-carbamimidoyl-2-fluorobenzyl)-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 1.23 (s, 6H), 2.93 (d, 1H, J=18.0 Hz), 3.38 (d,1H, J=17.6 Hz), 5.08-5.12 (m, 2H), 5.34 (d, 1H, J=14.4 Hz), 5.57 (s,2H), 5.64 (d, 1H, J=4.4 Hz), 6.75 (s, 1H), 6.92 (d, 1H, J=3.6 Hz), 7.15(t, 1H, J=7.6 Hz), 7.36 (d, 1H, J=7.2 Hz), 7.41 (d, 1H, J=10.4 Hz), 7.67(d, 1H, J=3.6 Hz), 7.77 (d, 1H, J=6.8 Hz), 8.27 (d, 1H, J=8.0 Hz), 9.05(s, 1H). Seven protons were not observed in D₂O.

Mass: ES⁺ 736.41

Example 9 (Table 1, Compound 17)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-{[1-({3-[(diaminomethylidene)amino]-1,2-oxazol-5-yl}methyl)-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 1.25 (s, 6H), 2.93 (d, 1H,

J=17.6 Hz), 3.42 (d, 1H, J=18.0 Hz), 5.07-5.10 (m, 2H), 5.39 (d, 1H,J=13.6 Hz), 5.61 (s, 2H), 5.64 (d, 1H, J=4.8 Hz), 6.10 (s, 1H), 6.78 (s,1H), 6.94 (d, 1H, J=3.2 Hz), 7.68 (d, 1H, J=3.6 Hz), 7.85 (d, 1H, J=6.4Hz), 8.38 (d, 1H, J=6.8 Hz), 9.09 (s, 1H). Eight protons were notobserved in D₂O.

Mass: ES⁺ 724.35

Example 10 (Table 1, Compound 18)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-({1-[(4-carbamimidoylthiophen-2-yl)methyl]-1H-imidazo[1,2-b]pyrazol-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

Step 1: 5-(1H-Imidazo[1,2-b]pyrazol-1-ylmethyl)thiophene-3-carbonitrile

To a stirred solution of 1H-imidazo[1,2-b]pyrazole (0.25 g, 2.33 mmol)in anhydrous dimethylformamide (5 mL) was added sodium hydride (60%dispersion in mineral oil, 0.14 g, 3.50 mmol) in small portions at 0° C.The reaction mixture was stirred at 0° C. for 30 min and a solution of5-(bromomethyl)thiophene-3-carbonitrile (0.495 g, 2.45 mmol) inanhydrous dimethylformamide (1.0 mL) was added slowly. The reactionmixture was stirred at 0° C. for 1 h then at room temperature for 2 h.The reaction was quenched using aqueous saturated ammonium chloridesolution (2 mL) and the resulting mixture was partitioned between ethylacetate (80 mL) and water (10 mL). The organic phase was separated,washed with water (10 mL), brine (10 mL), dried over sodium sulfate,filtered and concentrated under reduced pressure. The crude mixture waspurified by flash column chromatography (silica gel, 230-400 mesh) usinga 50 to 100% gradient of ethyl acetate in hexane to afford5-(1H-imidazo[1,2-b]pyrazol-1-ylmethyl)thiophene-3-carbonitrile (0.28 g,53%) as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 5.38 (s, 2H), 5.72 (d, 1H, J=1.9 Hz),7.29-7.32 (m, 1H), 7.46-7.48 (m, 1H), 7.57 (m, 2H), 8.49 (d, 1H, J=1.2Hz)

Mass: ES⁺ 229.09

Step 2: Ethyl5-(1H-imidazo[1,2-b]pyrazol-1-ylmethyl)thiophene-3-carboximidatehydrochloride

A solution of5-(1H-imidazo[1,2-b]pyrazol-1-ylmethyl)thiophene-3-carbonitrile (fromstep 1, 0.39 g, 1.71 mmol) in anhydrous ethanol (30 mL) at 0° C. waspurged with a stream of anhydrous hydrogen chloride gas for 15 min. Thereaction flask was stoppered and the reaction mixture was stirred atroom temperature for 24 h. The volatiles were removed under reducedpressure and the residue was further dried under high vacuum to affordethyl 5-(1H-imidazo[1,2-b]pyrazol-1-ylmethyl)thiophene-3-carboximidatehydrochloride (0.60 g, crude) as a yellow solid which was used directlyin the next step without further purification.

¹H NMR (400 MHz, DMSO-d₆): δ 1.45 (t, 3H, J=7.0 Hz), 4.55 (q, 2H, J=7.0Hz), 5.46 (s, 2H), 5.83 (d, 1H, J=1.9 Hz), 7.40 (s, 1H), 7.58 (s, 1H),7.65 (d, 1H, J=1.6 Hz), 7.81 (s, 1H), 8.78 (d, 1H, J=1.6 Hz). One protonwas not observed in DMSO

Mass: ES⁺ 275.16

Step 3:5-(1H-Imidazo[1,2-b]pyrazol-1-ylmethyl)thiophene-3-carboximidamide

A solution of ethyl5-(1H-imidazo[1,2-b]pyrazol-1-ylmethyl)thiophene-3-carboximidatehydrochloride (from step 2, crude, 0.6 g, 1.71 mmol) in anhydrousmethanol (20 mL) at 0° C. was purged with a stream of anhydrous ammoniagas for 15 min. The reaction flask was sealed and the reaction mixturewas allowed to warm to room temperature and stirred for 17 h. Thevolatiles were removed under reduced pressure and the residue wasfurther dried under high vacuum to afford5-(1H-imidazo[1,2-b]pyrazol-1-ylmethyl)thiophene-3-carboximidamide (1.0g, crude) as a reddish solid which was used in the next step withoutfurther purification.

¹HNMR (400 MHz, DMSO-d₆): δ 5.40 (s, 2H), 5.69 (d, 1H, J=1.9 Hz),7.29-7.32 (m, 1H), 7.44-7.48 (m, 1H), 7.59 (d, 1H, J=2.7 Hz), 7.69 (d,1H, J=0.8 Hz), 8.50 (d, 1H, J=1.6 Hz). Three protons were not observedin DMSO.

Mass: ES⁺ 246.09

Step 4: tert-Butyl{[5-(1H-imidazo[1,2-b]pyrazol-1-ylmethyl)thiophen-3-yl](imino)methyl}carbamate

To a vigorously stirred solution of5-(1H-imidazo[1,2-b]pyrazol-1-ylmethyl)thiophene-3-carboximidamide (fromstep 3, crude, 1.0 g, 1.71 mmol) in 1,4-dioxane (10 mL) was addedaqueous saturated sodium bicarbonate solution (6 mL) followed bydi-tert-butyl dicarbonate (1.5 g, 6.84 mmol). The reaction mixture wasstirred at room temperature for 17 h. The majority of 1,4-dioxane wasremoved under reduced pressure and the mixture was partitioned betweendichloromethane (50 mL) and water (30 mL). The phases were separated andthe aqueous layer was re-extracted with dichloromethane (60 mL). Thecombined organic extracts were dried over sodium sulfate, filtered andconcentrated under reduced pressure. The crude mixture was purified byflash column chromatography (silica gel, 230-400 mesh) using a 30 to100% gradient of ethyl acetate in hexane to afford tert-butyl{[5-(1H-imidazo[1,2-b]pyrazol-1-ylmethyl)thiophen-3-yl](imino)methyl}carbamate(0.215 g, 36% over 3 steps) as a yellowish solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.41 (s, 9H), 5.32 (s, 2H), 5.65 (d, 1H,J=1.9 Hz), 7.24-7.30 (m, 1H), 7.39-7.46 (m, 1H), 7.54 (d, 1H, J=1.9 Hz),7.60 (d, 1H, J.8 Hz), 8.21 (d, 1H, J=1.2 Hz), 8.85 (br s, 2H)

Mass: ES⁺346.23, ES⁻ 344.18

Step 5:5-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-Butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-{[(1-tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy]imino}acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-({4-[N-(tert-butoxycarbonyl)carbamimidoyl]thiophen-2-yl}methyl)-1H-imidazo[1,2-b]pyrazol-5-iumiodide

To a solution of tert-butyl{[5-(1H-imidazo[1,2-b]pyrazol-1-ylmethyl)thiophen-3-yl](imino)methyl}carbamate(from step 4, 0.118 g, 0.34 mmol) in anhydrous dimethylformamide (2 mL)was added(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-{[(1-tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy]imino}acetyl]amino}-3-(iodomethyl)-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-5-olate(0.303 g, 0.34 mmol) in one portion at room temperature. The reactionmixture was stirred at room temperature for 18 h. Anhydrousdimethylformamide (1 mL) was added and the reaction mixture was cooledto −40° C. Potassium iodide (0.317 g, 2.39 mmol) followed by acetylchloride (0.107 g, 1.37 mmol) was then added at −40° C. and the reactionmixture was stirred at 0° C. for 1 h. Aqueous 5% sodium bisulphitesolution (containing sodium metabisulphite, 10 mL) was added and theresulting mixture was stirred for 15 min at room temperature. Theprecipitated solid was collected by filtration, washed with water (3×10mL) and air-dried. The crude product was further dried under high vacuumto afford5-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-{[(1-tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy]imino}acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-({4-[N-(tert-butoxycarbonyl)carbamimidoyl]thiophen-2-yl}methyl)-1H-imidazo[1,2-b]pyrazol-5-iumiodide (0.37 g, crude) as a yellow solid which was used in the next stepwithout further purification.

Mass: ES⁺ 1090.75

Step 6:(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-({1-[(4-carbamimidoylthiophen-2-yl)methyl]-1H-imidazo[1,2-b]pyrazol-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

To a stirred solution of5-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-{[(1-tert-butoxy-2-methyl-1-oxopropan-2-yl)oxy]imino}acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-({4-[N-(tert-butoxycarbonyl)carbamimidoyl]thiophen-2-yl}methyl)-1H-imidazo[1,2-b]pyrazol-5-iumiodide (0.37 g, 0.30 mmol) and anisole (1 mL) in anhydrousdichloromethane (7 mL) was added trifluoroacetic acid (3 mL) dropwise at0° C. The reaction mixture was allowed to warm to room temperature andstirred for 3 h. The volatiles were then removed under reduced pressureand the residue was triturated using diisopropyl ether (15 mL). Theprecipitate was collected by filtration, washed with diisopropyl ether(5 mL) and dried under high vacuum to afford a yellow solid (0.33 g).The crude material was then taken in distilled water (20 mL) and theresulting suspension was stirred vigorously for 30 min at roomtemperature. The insoluble material was filtered off, the filtrate wascollected and lyophilized. The crude product (0.16 g) was purified byprep HPLC to afford the trifluoroacetic acid salt of(6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-({1-[(4-carbamimidoylthiophen-2-yl)methyl]-1H-imidazo[1,2-b]pyrazol-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate(15 mg; 6% over 2 steps).

¹H NMR (400 MHz, D₂O): δ 1.27 (s, 3H), 1.29 (s, 3H), 2.92 (d, 1H, J=18.0Hz), 3.25 (d, 1H, J=18.0 Hz), 5.03 (d, 1H, J=5.1 Hz), 5.13 (s, 2H), 5.44(s, 2H), 5.61 (d, 1H, J=4.7 Hz), 6.19 (d, 1H, J=3.5 Hz), 6.83 (s, 1H),7.38-7.42 (m, 2H), 7.85-7.87 (m, 1H), 7.88 (d, 1H, J=4.3 Hz), 8.14 (s,1H). Seven protons were not observed in D₂O.

Mass: ES⁺ 712.37

Example 11 (Table 1, Compound 59)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-({1-[(4-carbamimidoylthiophen-2-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

Step 1:5-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-Butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-({4-[N-(tert-butoxycarbonyl)carbamimidoyl]thiophen-2-yl}methyl)-1H-pyrrolo[3,2-c]pyridin-5-iumiodide

To a solution tert-butyl{[5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)thiophen-3-yl]carbonoimidoyl}carbamate(0.12 g, 0.30 mmol) in dimethylformamide (2 mL) was added4-methoxybenzyl(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate(0.19 g, 0.30 mmol) at 0° C. The reaction mixture was then degassedunder reduced pressure for 0.5 h, followed by adding Nal (0.09 g, 0.6mmol) and stirred at room temperature overnight. Sodium bisulphite (0.6g) in sodium chloride solution (75 mL) was added at 15° C. and stirredfor 10 minutes. The solid was filtered, washed with water and driedunder vacuum to a yellow solid (0.29 g), which was used in the next stepwithout further purification.

Step 2:(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-({1-[(4-carbamimidoylthiophen-2-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

To a solution of5-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-({4-[N-(tert-butoxycarbonyl)carbamimidoyl]thiophen-2-yl}methyl)-1H-pyrrolo[3,2-c]pyridin-5-iumiodide (0.29 g) in dry dichloromethane (2.5 mL) at 0° C. was addedtrifluoroacetic acid (2.5 mL) and anisole (0.82 mL, 7.75 mmol) and thenstirred at room temperature for 2 h. Solvent was evaporated anddiisopropyl ether (30 mL) was added. The solid separated was filtered,washed with di-isopropyl ether and dried under vacuum. The greenishyellow solid (315 mg) was dissolved in water (30 mL), filtered and theaqueous phase was lyophilized to give yellow solid (160 mg) which waspurified by preparative HPLC to give(6R,7R)-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-({1-[(4-carbamimidoylthiophen-2-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylateas formic acid salt (0.007 g, 4%).

¹H NMR (400 MHz, D₂O): δ 3.05 (d, 1H, J=17.6 Hz), 3.45 (d, 1H, J=18.0Hz), 3.84 (s, 3H), 5.11 (d, 1H, J=4.8 Hz), 5.21 (d, 1H, J=14.8 Hz), 5.35(d, 1H, J=14.4 Hz), 5.70 (m, 3H), 6.84 (s, 1H), 6.98 (d, 1H, J=3.2 Hz),7.34 (s, 1H), 7.73 (d, 1H, J=3.6 Hz), 7.88 (d, 1H, J=7.2 Hz), 8.12 (s,1H), 8.31 (d, 1H, J=8.4 Hz), 9.08 (s, 1H). Six protons were not observedin D₂O.

Mass: ES⁺ 652.15

Example 12 (Table 1, Compound 62)(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-8-oxo-3-[(1-{[4-(N-phenylcarbamimidoyl)thiophen-2-yl]methyl}-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl)methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

Step 1:N-phenyl-5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)thiophene-3-carboximidamide

To a solution of ethyl5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)thiophene-3-carboximidatehydrochloride (0.5 g, 1.55 mmol) and triethylamine (0.56 mL, 4.0 mmol)in ethanol (5 mL) was added aniline (0.2.33 mmol) at room temperature.The reaction mixture was stirred at room temperature for 2 days andconcentrated. The residue was purified by column chromatography usingmethanol: dichloromethane (15:85) as eluent to giveN-phenyl-5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)thiophene-3-carboximidamide(0.28 g, 54%) as a beige solid.

¹H NMR (400 MHz, CD₃OD): δ 5.78 (s, 2H), 6.81 (d, 1H, J=4.4 Hz),7.38-7.47 (m, 3H), 7.53-7.57 (m, 2H), 7.62 (m, 2H), 7.70 (d, 1H, J=6.4Hz), 8.23 (d, 1H, J=6.4 Hz), 8.35 (s, 1H), 8.87 (s, 1H). Two protonswere not observed in CD₃OD.

Step 2:5-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-Butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-{[4-(N-phenylcarbamimidoyl)thiophen-2-yl]methyl}-1H-pyrrolo[3,2-c]pyridin-5-iumiodide

To a solutionN-phenyl-5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)thiophene-3-carboximidamide(0.10 g, 0.30 mmol) in dimethylformamide (2 mL) was added4-methoxybenzyl(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate(0.21 g, 0.30 mmol) at 0° C. The reaction mixture was then degassedunder reduced pressure for 0.5 h, followed by adding Nal (0.09 g, 0.6mmol) and stirred at room temperature overnight. Sodium bisulphite (0.6g) in sodium chloride solution (75 mL) was added at 15° C. and stirredfor 10 minutes. The solid was filtered off, washed with water and driedunder vacuum to a yellow solid (0.28 g), which was used in the next stepwithout further purification.

Step 3:(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-8-oxo-3-[(1-{[4-(N-phenylcarbamimidoyl)thiophen-2-yl]methyl}-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl)methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

To a solution of5-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-{[4-(N-phenylcarbamimidoyl)thiophen-2-yl]methyl}-1H-pyrrolo[3,2-c]pyridin-5-iumiodide (0.28 g) in dry dichloromethane (2.5 mL) at 0° C. was addedtrifluoroacetic acid (2.5 mL) and anisole (0.82 mL, 7.75 mmol) and thenstirred at room temperature for 2 h. Solvent was evaporated anddiisopropyl ether (30 mL) was added. The solid was filtered, washed withdiisopropyl ether and dried under vacuum. The greenish yellow solid (315mg) was dissolved in water (30 mL), filtered and the aqueous phase waslyophilized to give yellow solid (160 mg) which was purified bypreparative HPLC to give(6R,7R)-7-{[(2Z)-2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-8-oxo-3-[(1-{[4-(N-phenylcarbamimidoyl)thiophen-2-yl]methyl}-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl)methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate as formic acid salt (0.01 g, 5%).

¹H NMR (400 MHz, D₂O): δ 3.05 (d, 1H, J=18.0 Hz), 3.43 (d, 1H, J=18.0Hz), 3.84 (s, 3H), 5.10 (d, 1H, J=4.8 Hz), 5.22 (d, 1H, J=15.2 Hz), 5.35(d, 1H, J=14.4 Hz), 5.71 (d, 1H, J=4.8 Hz), 5.76 (s, 2H), 7.00 (d, 1H,J=3.2 Hz), 7.30 (d, 2H, J=7.2 Hz), 7.41-7.49 (m, 4H), 7.78 (d, 1H, J=3.2Hz), 7.92 (d, 1H, J=7.6 Hz), 8.21 (s, 1H), 8.33 (d, 1H, J=8.0 Hz), 9.09(s, 1H). Five protons were not observed in D₂O.

Mass: ES⁺ 662.09

Example 13 (Table 1, Compound 63)(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-8-oxo-3-[(1-{[4-(pyrrolidin-1-ylcarbonoimidoyl)thiophen-2-yl]methyl}-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl)methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

Step 1:1-(Pyrrolidin-1-yl)-1-[5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)thiophen-3-yl]methanimine

To a solution of ethyl5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)thiophene-3-carboximidatehydrochloride (0.5 g, 1.55 mmol) and triethylamine (0.56 mL, 4.0 mmol)in ethanol (5 mL) was added pyrrolidine (0.2 g, 2.81 mmol) at roomtemperature. The reaction mixture was stirred at room temperature for 2days and concentrated. The residue was purified by column chromatographyusing methanol: dichloromethane (15:85) as eluent to give1-(pyrrolidin-1-yl)-1-[5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)thiophen-3-yl]methanimine(0.26 g, 54%) as a beige solid.

¹H NMR (400 MHz, CD₃OD): δ 1.96 (m, 2H), 2.14 (m, 2H), 3.30 (m, 4H),5.64 (s, 2H), 6.74 (d, 1H, J=4.0 Hz), 7.38 (s, 1H), 7.51 (d, 1H, J=3.6Hz), 7.57 (d, 1H, J=6.0 Hz), 7.99 (s, 1H), 8.18 (d, 1H, J=5.6 Hz), 8.81(s, 1H). One proton was not observed in CD₃OD.

Step 2:5-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-Butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-{[4-(pyrrolidin-1-ylcarbonoimidoyl)thiophen-2-yl]methyl}-1H-pyrrolo[3,2-c]pyridin-5-iumiodide

To a solution1-(pyrrolidin-1-yl)-1-[5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)thiophen-3-yl]methanimine(0.093 g, 0.30 mmol) in dimethylformamide (2 mL) was added4-methoxybenzyl(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate(0.21 g, 0.30 mmol) at 0° C. The reaction mixture was then degassedunder reduced pressure for 0.5 h, followed by adding NaI (0.09 g, 0.6mmol) and stirred at room temperature overnight. Sodium bisulphite (0.6g) in sodium chloride solution (75 mL) was added at 15° C. and stirredfor 10 minutes. The solid separated was filtered, washed with water anddried under vacuum to a yellow solid (0.28 g), which was used in thenext step without further purification.

Step 3:(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-8-oxo-3-[(1-{[4-(pyrrolidin-1-ylcarbonoimidoyl)thiophen-2-yl]methyl}-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl)methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

To a solution of5-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-{[4-(pyrrolidin-1-ylcarbonoimidoyl)thiophen-2-yl]methyl}-1H-pyrrolo[3,2-c]pyridin-5-iumiodide (0.29 g) in dry dichloromethane (2.5 mL) at 0° C. was addedtrifluoroacetic acid (2.5 mL) and anisole (0.82 mL, 7.75 mmol) and thenstirred at room temperature for 2 h. Solvent was evaporated anddiisopropyl ether (30 mL) was added to the residue and the solidseparated was filtered, washed with diisopropyl ether then dried undervacuum. The greenish yellow solid (315 mg) was dissolved in water (30mL), filtered and the aqueous phase was lyophilized to give yellow solid(160 mg) which was purified by preparative HPLC to give(6R,7R)-7-{[(2Z)-2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-8-oxo-3-[(1-{[4-(pyrrolidin-1-ylcarbonoimidoyl)thiophen-2-yl]methyl}-H-pyrrolo[3,2-c]pyridin-5-ium-5-yl)methyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylateas formic acid salt (0.011 g, 5.7%).

¹H NMR (200 MHz, D₂O): δ 1.79 (m, 2H), 1.97 (m, 2H), 3.03 (d, 1H, J=18.0Hz), 3.42 (m, 5H), 3.84 (s, 3H), 5.10 (d, 1H, J=4.4 Hz), 5.21 (d, 1H,J=14.8 Hz), 5.35 (d, 1H, J=14.4 Hz), 5.70 (m, 3H), 6.98 (d, 1H, J=3.2Hz), 7.22 (s, 1H), 7.74 (d, 1H, J=3.2 Hz), 7.85 (s, 1H), 7.89 (d, 1H,J=7.2 Hz), 8.32 (d, 1H, 7.2 Hz), 9.08 (s, 1H). Four protons were notobserved in D₂O.

Mass: ES⁺ 740.13

Example 14 (Table 1, Compound 64)(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-8-oxo-3-{[1-({4-[N-(1,3-thiazol-2-yl)carbamimidoyl]thiophen-2-yl}methyl)-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl]methyl}-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

Step 1:5-(1H-Pyrrolo[3,2-c]pyridin-1-ylmethyl)-N-(1,3-thiazol-2-yl)thiophene-3-carboximidamide

To a solution of ethyl5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)thiophene-3-carboximidatehydrochloride (0.5 g, 1.55 mmol) and triethylamine (0.56 mL, 4.0 mmol)in ethanol (5 mL) was added 1,3-thiazol-2-amine (0.25 g, 2.33 mmol) atroom temperature. The reaction mixture was stirred at room temperaturefor 2 days and concentrated. The residue was purified by columnchromatography using methanol: dichloromethane (15:85) as eluent to give5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)-N-(1,3-thiazol-2-yl)thiophene-3-carboximidamide(0.22 g, 42%) as a beige solid.

¹H NMR (400 MHz, CD₃OD): δ 5.43 (s, 2H), 6.65 (d, 1H, J=4.0 Hz), 7.16(m, 2H), 7.27 (m, 2H), 7.44 (m, 1H, J=6.0 Hz), 7.64 (s, 1H), 8.32 (d,1H, J=6.0 Hz), 8.92 (s, 1H).

Step 2:5-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-Butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-({4-[N-(1,3-thiazol-2-yl)carbamimidoyl]thiophen-2-yl}methyl)-1H-pyrrolo[3,2-c]pyridin-5-iumiodide

To a solution of5-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)-N-(1,3-thiazol-2-yl)thiophene-3-carboximidamide(0.102 g, 0.30 mmol) in dimethylformamide (2 mL) was added4-methoxybenzyl(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate(0.21 g, 0.30 mmol) at 0° C. The reaction mixture was then degassedunder reduced pressure for 0.5 h, followed by adding NaI (0.09 g, 0.6mmol) and stirred at room temperature overnight. Sodium bisulphite (0.6g) in sodium chloride solution (75 mL) was added at 0° C., stirred for10 minutes and the solid separated was filtered, washed with water anddried under vacuum to a yellow solid (0.3 g), which was used in the nextstep without further purification.

Step 3:(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-8-oxo-3-{[1-({4-[N-(1,3-thiazol-2-yl)carbamimidoyl]thiophen-2-yl}methyl)-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl]methyl}-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

To a solution of5-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-({4-[N-(1,3-thiazol-2-yl)carbamimidoyl]thiophen-2-yl}methyl)-1H-pyrrolo[3,2-c]pyridin-5-iumiodide (0.3 g) in dry dichloromethane (2.5 mL) at 0° C. was addedtrifluoroacetic acid (2.5 mL) and anisole (0.82 mL, 7.75 mmol) and thenstirred at room temperature for 2 h, then the solvent was evaporated anddiisopropyl ether (30 mL) was added. The solid was filtered, washed withdiisopropyl ether and dried under vacuum. The greenish yellow solid (315mg) was dissolved in water (30 mL), filtered and the aqueous phase waslyophilized to give yellow solid (160 mg) which was purified bypreparative HPLC to give(6R,7R)-7-{[(2Z)-2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-8-oxo-3-{[1-({4-[N-(1,3-thiazol-2-yl)carbamimidoyl]thiophen-2-yl}methyl)-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl]methyl}-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylateas formic acid salt (0.005 g, 2.5%).

¹H NMR (400 MHz, D₂O): δ 3.03 (d, 1H, J=17.6 Hz), 3.43 (d, 1H, J=17.2Hz), 3.84 (s, 3H), 5.11 (d, 1H, J=4.8 Hz), 5.21 (d, 1H, J=13.6 Hz), 5.36(d, 1H, J=14.0 Hz), 5.72 (m, 3H), 7.01 (d, 1H, J=4.2 Hz), 7.25 (d, 1H,J=3.6 Hz), 7.41 (d, 1H, J=7.6 Hz), 7.49 (m, 1H), 7.75 (m, 1H), 7.92 (d,1H, J=7.2 Hz), 8.20 (s, 1H), 8.33 (d, 1H, J=7.6 Hz), 9.06 (s, 1H). Fiveprotons were not observed in D₂O.

Mass: ES⁺ 769.03

Example 15 (Table 1, Compound 60)(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-({1-[(4-carbamimidoylthiophen-2-yl)methyl]-1H-pyrrolo[3,2-b]pyridin-4-ium-4-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

Step 1: 5-(1H-Pyrrolo[3,2-b]pyridin-1-ylmethyl)thiophene-3-carbonitrile

To a solution of 1H-pyrrolo[3,2-b]pyridine (0.59 g, 5.00 mmol) inanhydrous dimethylformamide (10 mL) was added sodium hydride (60%suspension in mineral oil, 0.29 g, 7.25 mmol) at 0° C. in small portionsunder nitrogen. After the addition, the mixture was stirred for 10minutes at 0° C. and then at room temperature for 10 minutes, cooled to0° C. and was added 5-(bromomethyl)thiophene-3-carbonitrile (1.11 g,5.50 mmol) in anhydrous tetrahydrofuran (10 mL) dropwise. After theaddition, the reaction mixture was stirred at 0° C. for 1.5 h, quenchedwith ice-water (10 mL) and extracted with ethyl acetate (20 mL×2). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and evaporated. The residue was purified by columnchromatography using DCM: MeOH (92:8) as eluent to afford5-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)thiophene-3-carbonitrile (1.0 g,80%) as a brown solid.

¹H NMR (400 MHz, CDCl₃): δ 5.47 (s, 2H), 6.79 (d, 1H, J=4.0 Hz), 7.10(s, 1H), 7.12 (m, 1H), 7.36 (d, 1H, J=3.6 Hz), 7.58 (d, 1H, J=10.4 Hz),7.82 (s, 1H), 8.50 (d, 1H, J=6.0 Hz).

Step 2: Methyl5-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)thiophene-3-carboximidatehydrochloride

Anhydrous hydrogen chloride gas was bubbled through a solution of5-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)thiophene-3-carbonitrile (1.0 g,4.18 mmol) in anhydrous ethanol (30 mL) at 0° C. for 20 minutes. Thereaction mixture was stirred at room temperature for 20 h and thesolvent was evaporated and dried under vacuum to give methyl5-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)thiophene-3-carboximidatehydrochloride (0.97 g crude) as brown solid, which was used in next stepwithout further purification.

Step 3:5-(1H-Pyrrolo[3,2-b]pyridin-1-ylmethyl)thiophene-3-carboximidamide

Anhydrous ammonia gas was bubbled through a solution of methyl5-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)thiophene-3-carboximidatehydrochloride (0.97 g crude, ˜4.1 mmol) in anhydrous methanol (40 mL) at0° C. for 15 minutes. Then the reaction mixture was stirred at roomtemperature for 16 h. Solvent was evaporated and dried under vacuum togive 5-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)thiophene-3-carboximidamide(1.2 g, crude) as a brown solid which was used in the next step withoutfurther purification.

Step 4: tert-Butyl{[5-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)thiophen-3-yl]carbonoimidoyl}carbamate

To a solution of5-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)thiophene-3-carboximidamide (0.97g, crude) in 1,4-dioxane (100 mL) was added aqueous saturated sodiumcarbonate solution (50 mL) followed by di-tert-butyldicarbonate (3.30 g,15.12 mmol) at 0° C. The reaction mixture was stirred at roomtemperature for 16 h, the solvent was evaporated and was added water (50mL) was added then extracted with ethyl acetate (2×50 mL). The organicphases were combined, washed with brine (2×50 mL) and dried over Na₂SO₄.The solvent was evaporated and the crude compound was purified by flashchromatography using RediSep silica 40 g flash column (0-6% methanol inmethylene chloride as eluent) to give tert-butyl{[5-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)thiophen-3-yl]carbonoimidoyl}carbamate(1.2 g, 61% over three steps) as an off-white solid.

¹H NMR (400 MHz, CDCl₃): δ 1.51 (s, 9H), 5.39 (s, 2H), 6.66 (d, 1H,J=4.00 Hz), 7.06 (m, 1H), 7.32 (d, 1H, J=3.2 Hz), 7.42 (s, 1H), 7.58 (d,1H, J=10.4 Hz), 7.87 (s, 1H), 8.42 (d, 1H, J=5.6 Hz).

Step 5:4-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-Butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-({4-[N-(tert-butoxycarbonyl)carbamimidoyl]thiophen-2-yl}methyl)-1H-pyrrolo[3,2-b]pyridin-4-iumiodide

To a solution tert-butyl{[5-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)thiophen-3-yl]carbonoimidoyl}carbamate(0.12 g, 0.30 mmol) in dimethylformamide (2 mL) was added4-methoxybenzyl(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate(0.21 g, 0.30 mmol) at 0° C. The reaction mixture was then degassedunder reduced pressure for 0.5 h, followed by adding NaI (0.09 g, 0.6mmol) and stirred at room temperature overnight. Sodium bisulphite (0.6g) in sodium chloride solution (75 mL) was added at 15° C. and stirredfor 10 minutes. The solid was filtered, washed with water and driedunder vacuum to a yellow solid (0.3 g), which was used in the next stepwithout further purification.

Step 6:(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-({1-[(4-carbamimidoylthiophen-2-yl)methyl]-1H-pyrrolo[3,2-b]pyridin-4-ium-4-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

To a solution of4-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-({4-[N-(tert-butoxycarbonyl)carbamimidoyl]thiophen-2-yl}methyl)-1H-pyrrolo[3,2-b]pyridin-4-iumiodide (0.3 mg, crude)) in dry dichloromethane (2.5 mL) at 0° C. wasadded trifluoroacetic acid (2.5 mL) and anisole (0.82 mL, 7.75 mmol) andthen stirred at room temperature for 2 h. Solvent was evaporated,diisopropyl ether (30 mL) was added, and the solid separated wasfiltered, washed with diisopropyl ether and dried under vacuum. Thegreenish yellow solid (315 mg) was dissolved in water (30 mL), filteredand the aqueous phase was lyophilized to give yellow solid (165 mg),which was purified by preparative HPLC to give(6R,7R)-7-{[(2Z)-2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-({1-[(4-carbamimidoylthiophen-2-yl)methyl]-1H-pyrrolo[3,2-b]pyridin-4-ium-4-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylateas formic acid salt (0.007 g, 3.9%).

¹H NMR (400 MHz, D₂O): δ 3.08 (d, 1H, J=18.0 Hz), 3.23 (d, 1H, J=17.6Hz), 3.86 (s, 3H), 5.04 (d, 1H, J=4.8 Hz), 5.39 (d, 1H, J=15.2 Hz), 5.67(d, 1H, J=14.8 Hz), 5.71 (d, 1H, J=4.4 Hz), 5.76 (s, 2H), 6.93 (d, 1H,J=3.6 Hz), 7.35 (s, 1H), 7.55 (m, 1H), 8.09 (d, 1H, J=3.2 Hz), 8.13 (s,1H), 8.49 25 (m, 2H). Six protons were not observed in D₂O.

Mass: ES⁺ 686.14

Example 16 (Table 1, Compound 61)(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-({1-[(4-carbamimidoylthiophen-2-yl)methyl]-1H-pyrrolo[2,3-c]pyridin-6-ium-6-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

Step 1: 5-(1H-Pyrrolo[2,3-c]pyridin-1-ylmethyl)thiophene-3-carbonitrile

To a solution of 1H-pyrrolo[2,3-c]pyridine (0.59 g, 5.00 mmol) inanhydrous dimethylformamide (10 mL) was added sodium hydride (60%suspension in mineral oil, 0.29 g, 7.25 mmol) at 0° C. in small portionsunder nitrogen. After the addition, reaction mixture was stirred for 10minutes at 0° C., then at room temperature for 10 minutes, cooled to 0°C. then 5-(bromomethyl)thiophene-3-carbonitrile (1.11 g, 5.50 mmol) inanhydrous tetrahydrofuran (10 mL) was added dropwise. After theaddition, reaction mixture was stirred at 0° C. for 1.5 h, quenched withice-water (10 mL) and extracted with ethyl acetate (20 mL×2). Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered and evaporated. The residue was purified by columnchromatography using DCM: MeOH (92:8) as eluent to afford5-(1H-pyrrolo[2,3-c]pyridin-1-ylmethyl)thiophene-3-carbonitrile (0.88 g,73%) as a brown solid. ¹H NMR (400 MHz, CDCl₃): δ 5.56 (s, 2H), 6.59 (d,1H, J=2.8 Hz), 7.13 (s, 1H), 7.27 (d, 1H, J=6.8 Hz), 7.54 (d, 1H, J=5.2Hz), 7.82 (s, 1H), 8.29 (d, 1H, J=5.2 Hz), 8.73 (s, 1H).

Step 2: Methyl5-(1H-pyrrolo[2,3-c]pyridin-1-ylmethyl)thiophene-3-carboximidatehydrochloride

Anhydrous hydrogen chloride gas was bubbled through a solution of5-(1H-pyrrolo[2,3-c]pyridin-1-ylmethyl)thiophene-3-carbonitrile (0.8 g,3.34 mmol) in anhydrous ethanol (30 mL) at 0° C. for 20 minutes. Thenthe reaction mixture was stirred at room temperature for 20 h. Solventwas evaporated and dried under vacuum to give methyl5-(1H-pyrrolo[2,3-c]pyridin-1-ylmethyl)thiophene-3-carboximidatehydrochloride (1.0 g, crude) as brown solid, which was used in next stepwithout further purification.

Step 3: 5-(1H-Pyrrolo[2,3-c]pyridin-1-ylmethyl)thiophene-3-carbonitrile

Anhydrous ammonia gas was bubbled through a solution of methyl5-(1H-pyrrolo[2,3-c]pyridin-1-ylmethyl)thiophene-3-carboximidatehydrochloride (1.0 g crude, ˜4.1 mmol) in anhydrous methanol (40 mL) at0° C. for 15 minutes. The reaction mixture was stirred at roomtemperature for 16 h. Solvent was evaporated and dried under vacuum togive 5-(1H-pyrrolo[2,3-c]pyridin-1-ylmethyl)thiophene-3-carboximidamide(0.73 g, crude) as a brown solid, which was used in the next stepwithout further purification.

Step 4: tert-Butyl{[5-(1H-pyrrolo[2,3-c]pyridin-1-ylmethyl)thiophen-3-yl]carbonoimidoyl}carbamate

To a solution of5-(1H-pyrrolo[2,3-c]pyridin-1-ylmethyl)thiophene-3-carboximidamide (0.73g crude) in 1,4-dioxane (100 mL) was added aqueous saturated sodiumcarbonate solution (50 mL) followed by di-tert-butyldicarbonate (2.9 g,13.12 mmol) at 0° C. and stirred at room temperature for 16 h. Thesolvent was evaporated and was added water (50 mL) then extracted withethyl acetate (2×50 mL). The organic phases were combined, washed withbrine (2×50 mL), dried over Na₂SO₄, concentrated and the crude compoundwas purified by flash chromatography using RediSep silica 40 g flashcolumn (0-6% methanol in methylene chloride as eluent) to givetert-butyl{[5-(1H-pyrrolo[2,3-c]pyridin-1-ylmethyl)thiophen-3-yl]carbonoimidoyl}carbamate(1.0 g, 51% over three steps) as an off-white solid.

¹H NMR (400 MHz, CDCl₃): δ 1.53 (s, 9H), 5.50 (s, 2H), 6.54 (d, 1H,J=3.2 Hz), 6.88 (d, 1H, J=3.6 Hz), 7.26 (s, 1H), 7.37 (d, 1H, J=3.6 Hz),7.43 (s, 1H), 7.52 (d, 1H, J=4.8 Hz), 7.84 (s, 1H), 8.25 (d, 1H, J=5.6Hz), 8.78 (s, 1H).

Step 5:6-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-Butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-({4-[N-(tert-butoxycarbonyl)carbamimidoyl]thiophen-2-yl}methyl)-1H-pyrrolo[2,3-c]pyridin-6-iumiodide

To a solution tert-butyl{[5-(1H-pyrrolo[2,3-c]pyridin-1-ylmethyl)thiophen-3-yl]carbonoimidoyl}carbamate(0.12 g, 0.30 mmol) in dimethylformamide (2 mL) was added4-methoxybenzyl(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl})-2-(methoxyimino)acetyl]amino}-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (0.21 g, 0.30 mmol)at 0° C. The reaction mixture was then degassed under reduced pressurefor 0.5 h, treated with NaI (0.09 g, 0.6 mmol) and stirred at roomtemperature overnight.

Sodium bisulphite (0.6 g) in sodium chloride solution (75 mL) was addedto the reaction mixture at 15° C., stirred for 10 minutes and the solidseparated was filtered, washed with water then dried under vacuum to ayellow solid (0.3 g), which was used in the next step without furtherpurification.

Step 6:(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-({1-[(4-carbamimidoylthiophen-2-yl)methyl]-1H-pyrrolo[2,3-c]pyridin-6-ium-6-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylateformic acid salt

To a solution of6-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-({4-[N-(tert-butoxycarbonyl)carbamimidoyl]thiophen-2-yl}methyl)-1H-pyrrolo[2,3-c]pyridin-6-iumiodide (0.3 mg, crude)) in dry dichloromethane (2.5 mL) at 0° C. wasadded trifluoroacetic acid (2.5 mL) and anisole (0.82 mL, 7.75 mmol)then stirred at room temperature for 2 h. Solvent was evaporated,diisopropyl ether (30 mL) was added and solid was filtered, washed withdiisopropyl ether then dried under vacuum. The greenish yellow solid(315 mg) was dissolved in water (30 mL), filtered and the aqueous phasewas lyophilized to give yellow solid, which was purified by preparativeHPLC to get(6R,7R)-7-{[(2Z)-2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-({1-[(4-carbamimidoylthiophen-2-yl)methyl]-1H-pyrrolo[2,3-c]pyridin-6-ium-6-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylateyellow solid (165 mg) as formic acid salt (0.02 g, 11.2%).

¹H NMR (400 MHz, D₂O): δ 2.99 (d, 1H, J=18.0 Hz), 3.38 (d, 1H, J=18.0Hz), 3.85 (s, 3H), 5.06 (d, 1H, J=5.2 Hz), 5.13 (d, 1H, J=14.4 Hz), 5.34(d, 1H, J=14.0 Hz), 5.69-5.82 (m, 3H), 6.88 (d, 1H, J=3.2 Hz), 7.49 (s,1H), 7.96 (d, 1H, J=6.8 Hz), 8.14 (d, 1H, J=6.8 Hz), 8.32 (s, 2H), 9.06(s, 1H), Six protons were not observed in D₂O.

Mass: ES⁺ 686.23

Example 17 (Table 1, Compound 28)(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-({1-[(4-carbamimidoylthiophen-2-yl)methyl]-1H-imidazo[1,2-b]pyrazol-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O) δ 1.24 (s, 3H), 1.27 (s, 3H), 2.88 (d, 1H, J=18.0Hz), 3.24 (d, 1H, J=18.0 Hz), 5.02 (d, 1H, J=4.7 Hz), 5.13 (m, 2H), 5.45(s, 2H), 5.61 (d, 1H, J=4.7 Hz), 6.20 (d, 1H, J=3.9 Hz), 7.40 (s, 2H),7.87-7.89 (m, 2H), 8.14 (s, 1H). Seven protons were not observed in D₂O.

Mass: ES⁺ 747.34 and 749.22

Example 18 (Table 1, Compound 4)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-{[1-(4-carbamimidamidobenzyl)-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 1.27 (s, 3H), 1.28 (s, 3H), 2.92 (d, 1H, J=17.6Hz), 3.38 (d, 1H, J=17.6 Hz), 5.08-5.12 (m, 2H), 5.33 (d, 1H, J=14.9Hz), 5.44 (s, 2H), 5.64 (s, 1H), 6.80 (s, 1H), 6.91 (s, 1H), 7.11-7.17(m, 4H), 7.67-7.71 (m, 2H), 8.16 (s, 0.4H, formic acid), 8.25 (m, 1H),9.04 (s, 1H). Eight protons were not observed in D₂O.

Mass: ES⁺ 733.32

Example 19 (Table 1, Compound 7)(6R,7R)-3-[(1-{4-[N-(2-Aminoethyl)carbamimidoyl]benzyl}-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl)methyl]-7-{[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 1.20 (s, 3H), 1.21 (s, 3H), 2.92 (d, 1H, J=18.0Hz), 3.21 (t, 2H, J=6.3 Hz), 3.38 (d, 1H, J=18.0 Hz), 3.63 (t, 2H, J=6.3Hz), 5.06-5.11 (m, 2H), 5.32 (d, 1H, J=14.4 Hz), 5.52 (s, 2H), 5.59 (d,1H, J=4.7 Hz), 6.73 (s, 1H), 6.92 (d, 1H, J=3.1 Hz), 7.21 (d, 2H, J=8.2Hz), 7.52 (d, 2H, J=8.2 Hz), 7.66-7.69 (m, 2H), 8.23 (d, 1H, J=7.0 Hz),9.05 (s, 1H). Eight protons were not observed in D₂O.

Mass: ES⁺ 761.13

Example 20 (Table 1, Compound 8)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-({1-[4-(4,5-dihydro-1H-imidazol-2-yl)benzyl]-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 1.24 (s, 3H), 1.27 (s, 3H), 2.94 (d, 1H, J=17.5Hz), 3.40 (d, 1H, J=17.5 Hz), 3.89 (s, 4H), 5.09-5.13 (m, 2H), 5.34 (d,1H, J=14.8 Hz), 5.55 (s, 2H), 5.63 (d, 1H, J=4.7 Hz), 6.78 (s, 1H), 6.96(s, 1H), 7.23 (d, 2H, J=7.1 Hz), 7.58 (d, 2H, J=7.1 Hz), 7.69-7.71 (m,2H), 8.19 (s, 1H, formic acid), 8.25 (d, 1H, J=7.1 Hz), 9.08 (s, 1H).Five protons were not observed in D₂O.

Mass: ES⁺ 744.27

Example 21 (Table 1, Compound 12)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-({1-[2-(4-carbamimidamidophenyl)ethyl]-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 1.30 (s, 6H), 2.80 (d, 1H, J=17.6 Hz), 3.00 (m,2H), 3.23 (d, 1H, J=17.6 Hz), 4.44 (m, 2H), 5.03-5.07 (m, 2H), 5.21 (d,1H, J=14.1 Hz), 5.56 (d, 1H, J=4.3 Hz), 6.75-6.86 (m, 6H), 7.02 (d, 1H,J=6.7 Hz), 7.60 (s, 1H), 7.85 (d, 1H, J=6.7 Hz), 8.19 (s, 0.5H, formicacid), 8.90 (s, 1H). Eight protons were not observed in D₂O.

Mass: ES⁺ 747.27

Example 22 (Table 1, Compound 16)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-({1-[(4-carbamimidoyl-1,3-thiazol-2-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 1.29 (s, 3H), 1.32 (s, 3H), 2.98 (d, 1H, J=17.6Hz), 3.40 (d, 1H, J=17.6 Hz), 5.09 (d, 1H, J=4.7 Hz), 5.14 (d, 1H,J=14.4 Hz), 5.34 (d, 1H, J=14.4 Hz), 5.67 (d, 1H, J=4.7 Hz), 5.85 (s,2H), 6.91 (s, 1H), 6.97 (d, 1H, J=3.1 Hz), 7.74 (d, 1H, J=3.1 Hz), 7.86(d, 1H, J=7.1 Hz), 8.09 (s, 0.4H, formic acid), 8.31 (d, 1H, J=7.1 Hz),8.39 (s, 1H), 9.08 (s, 1H). Seven protons were not observed in D₂O.

Mass: ES⁺ 725.37

Example 23 (Table 1, Compound 19)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-({1-[4-(N′-methoxycarbamimidoyl)benzyl]-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 1.25 (s, 3H), 1.26 (s, 3H), 2.94 (d, 1H, J=18.0Hz), 3.35 (d, 1H, J=18.0 Hz), 3.64 (s, 3H), 5.07 (d, 1H, J=4.7 Hz), 5.09(d, 1H, J=14.5 Hz), 5.30 (d, 1H, J=14.5 Hz), 5.45 (s, 2H), 5.65 (d, 1H,J=4.7 Hz), 6.77 (s, 1H), 6.91 (d, 1H, J=3.5 Hz), 7.11 (d, 2H, J=8.2 Hz),7.38 (d, 2H, J=8.2 Hz), 7.64 (d, 1H, J=3.5 Hz), 7.69 (d, 1H, J=6.7 Hz),8.19 (d, 1H, J=6.7 Hz), 8.26 (s, 3H, formic acid), 9.02 (s, 1H). Sixprotons were not observed in D₂O.

Mass: ES⁺ 748.45

Example 24 (Table 1, Compound 30)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-({1-[(4-carbamimidoyl-1,3-oxazol-2-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 1.30 (s, 3H), 1.32 (s, 3H), 2.98 (d, 1H, J=18.0Hz), 3.39 (d, 1H, J=18.0 Hz), 5.08 (d, 1H, J=4.7 Hz), 5.14 (d, 1H,J=14.9 Hz), 5.33 (d, 1H, J=14.9 Hz), 5.66 (d, 1H, J=4.7 Hz), 5.71 (s,2H), 6.92 (s, 1H), 6.95 (d, 1H, J=3.5 Hz), 7.69 (d, 1H, J=3.5 Hz), 7.85(d, 1H, J=7.0 Hz), 8.31 (d, 1H, J=7.0 Hz), 8.50 (s, 1H), 9.06 (s, 1H).Seven protons were not observed in D₂O.

Mass: ES⁺ 709.29

Example 25 (Table 1, Compound 31)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-({1-[(4-{N-[(Z)-(dimethylamino)methylidene]carbamimidoyl}-1,3-oxazol-2-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 1.29 (s, 3H), 1.3 (s, 3H), 2.98 (d, 1H, J=18.0Hz), 3.05 (s, 3H), 3.13 (s, 3H), 3.40 (d, 1H, J=18.0 Hz), 5.08 (d, 1H,J=4.7 Hz), 5.13 (d, 1H, J=14.9 Hz), 5.34 (d, 1H, J=14.9 Hz), 5.65 (d,1H, J=4.7 Hz), 5.71 (s, 2H), 6.87 (s, 1H), 6.95 (d, 1H, J=3.2 Hz), 7.70(d, 1H, J=3.6 Hz), 7.86 (d, 1H, J=7.4 Hz), 8.23 (s, 1H), 8.32 (d, 1H,J=6.7 Hz), 8.45 (s, 1H), 9.08 (s, 1H). Five protons were not observed inD₂O.

Mass: ES⁺ 764.36

Example 26 (Table 1, Compound 29)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-[(1-{[3-(4,5-dihydro-1H-imidazol-2-yl)-1,2-oxazol-5-yl]methyl}-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 1.25 (s, 6H), 2.94 (d, 1H, J=17.2 Hz), 3.40 (d,1H, J=17.2 Hz), 4.59 (s, 4H), 5.08-5.13 (m, 2H), 5.35 (d, 1H, J=14.4Hz), 5.63 (d, 1H, J=5.1 Hz), 5.74 (s, 2H), 6.72 (m, 2H), 6.94 (d, 1H,J=1.2 Hz), 7.68 (d, 1H, J=3.1 Hz), 7.86 (d, 1H, J=7.1 Hz), 8.23 (s, 1H,formic acid), 8.34 (d, 1H, J=7.1 Hz), 9.07 (s, 1H). Five protons werenot observed in D₂O.

Mass: ES⁺ 735.21

Example 27 (Table 1, Compound 15)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-{[1-(4-carbamimidoyl-2-fluorobenzyl)-1H-imidazo[1,2-b]pyrazol-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 1.29 (s, 3H), 1.31 (s, 3H), 2.95 (d, 1H, J=17.6Hz), 3.24 (d, 1H, J=17.6 Hz), 5.04 (d, 1H, J=4.8 Hz), 5.14 (s, 2H), 5.37(s, 2H), 5.62 (d, 1H, J=4.8 Hz), 6.23 (d, 1H, J=3.2 Hz), 6.92 (s, 1H),7.40-7.48 (m, 4H), 7.84 (d, 1H, J=2.0 Hz), 7.88 (d, 1H, J=3.6 Hz). Sevenprotons were not observed in D₂O.

Mass: ES⁺ 725.42

Example 28 (Table 1, Compound 6)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-({1-[4-(2-carbamimidamidoethoxy)benzyl]-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, DMSO-d₆): δ 1.38 (s, 6H), 2.91 (d, 1H, J=18.4 Hz),3.20-3.50 (m, 3H), 3.92 (s, 1H), 4.02 (s, 1H), 4.85 (d, 1H, J=13.2 Hz),5.04 (d, 1H, J=5.2 Hz), 5.46 (s, 2H), 5.68 (d, 1H, J=13.2 Hz), 5.79 (d,1H, J=4.8 Hz), 6.72 (s, 1H), 6.81 (d, 2H, J=8.8 Hz), 7.03 (d, 1H, J=3.2Hz), 7.17 (s, 1H), 7.30 (d, 2H, J=8.0 Hz), 8.05 (d, 1H, J=6.0 Hz), 8.14(s, 1H), 9.30 (br s, 1H), 9.44 (s, 1H). Eight protons were not observedin D₂O.

Mass: ES⁺ 777.25

Example 29 (Table 1, Compound 20)(6R,7R)-7-{[(2Z)-2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-{[1-(4-carbamimidoyl-2-fluorobenzyl)-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

1H NMR (400 MHz, D₂O): δ 1.25 (s, 6H), 2.93 (d, 1H, J=17.6 Hz), 3.37 (d,1H, J=18.0 Hz), 5.08-5.12 (m, 2H), 5.33 (d, 1H, J=14.4 Hz), 5.57 (s,2H), 5.65 (d, 1H, J=4.4 Hz), 6.92 (d, 1H, J=3.6 Hz), 7.14 (t, 1H, J=8.0Hz), 7.36 (d, 1H, J=8.4 Hz), 7.41 (d, 1H, J=10.0 Hz), 7.66 (d, 1H, J=3.2Hz), 7.77 (d, 1H, J=6.8 Hz), 8.26 (d, 1H, J=6.8 Hz), 9.05 (s, 1H). Sevenprotons were not observed in D₂O.

Mass: ES⁺ 737.36

Example 30 (Table 1, Compound 21)(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-{[1-(4-carbamimidoyl-2-fluorobenzyl)-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 1.22 (s, 6H), 2.92 (d, 1H, J=18.0 Hz), 3.37 (d,1H, J=19.2 Hz), 5.07-5.11 (m, 2H), 5.34 (d, 1H, J=14.4 Hz), 5.58 (s,2H), 5.64 (d, 1H, J=4.4 Hz), 6.93 (d, 1H, J=4.0 Hz), 7.17 (t, 1H, J=7.6Hz), 7.36 (d, 1H, J=8.8 Hz), 7.42 (d, 1H, J=10.0 Hz), 7.67 (d, 1H, J=3.6Hz), 7.78 (d, 1H, J=6.4 Hz), 8.25 (d, 1H, J=6.8 Hz), 9.05 (s, 1H). Sevenprotons were not observed in D₂O.

Mass: ES⁺ 770.36

Example 31 (Table 1, Compound 26)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-({1-[(4-carbamimidoyl-1,3-thiazol-2-yl)methyl]-1H-imidazo[1,2-b]pyrazol-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 1.26 (s, 3H), 1.28 (s, 3H), 2.91 (d, 1H, J=18Hz), 3.28 (d, 1H, J=18 Hz), 5.08 (s, 1H), 5.15 (s, 1H), 5.18 (s, 1H),5.60-5.70 (m, 3H), 6.32 (s, 1H), 6.79 (s, 1H), 7.48 (s, 1H), 7.92-8.00(m, 2H), 8.44 (s, 1H). 65 Seven protons were not observed in D₂O.

Mass: ES⁺ 714.27

Example 32 (Table 1, Compound 22)(6R,7R)-7-({(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-[(carboxymethoxy)imino]acetyl}amino)-3-{[1-(4-carbamimidoyl-2-fluorobenzyl)-1H-imidazo[1,2-b]pyrazol-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 2.97 (d, 1H, J=18 Hz), 3.25 (d, 1H, J=18 Hz),5.04 (s, 1H), 5.15 (s, 2H), 5.38 (s, 2H), 5.66 (s, 1H), 6.23 (s, 1H),6.96 (s, 1H), 7.38-7.52 (m, 4H), 7.83 (s, 1H), 7.88 (s, 1H). Sevenprotons were not observed in D₂O.

Mass: ES⁺ 697.34

Example 33 (Table 1, Compound 23)(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-{[1-(4-carbamimidoyl-2-fluorobenzyl)-1H-imidazo[1,2-b]pyrazol-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 1.27 (s, 3H), 1.30 (s, 3H), 2.90 (d, 1H, J=18Hz), 3.20 (d, 1H, J=18 Hz), 5.00 (d, 1H, J=5.0 Hz), 5.13 (s, 2H), 5.32(s, 2H), 5.61 (d, 1H, J=5.0 Hz), 6.24 (s, 1H), 7.40-7.55 (m, 4H), 7.90(d, 2H, J=4.0 Hz), 8.20 (s, 0.2H). Six protons were not observed in D₂O.

Mass: ES⁺ 760.29

Example 34 (Table 1, Compound 24)(6R,7R)-7-{[(2Z)-2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-{[1-(4-carbamimidoyl-2-fluorobenzyl)-1H-imidazo[1,2-b]pyrazol-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 1.25 and 1.29 (2s, 6H), 2.90 (d, 1H, J=18 Hz),3.24 (d, 1H, J=18 Hz), 5.06 (s, 1H), 5.16 (s, 2H), 5.38 (s, 2H), 5.64(s, 1H), 6.25 (s, 1H), 7.40-7.50 (m, 4H), 7.90 (s, 2H), 8.27 (s, 2.75H).Six protons were not observed in D₂O.

Mass: ES⁺ 726.27

Example 35 (Table 1, Compound 25)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-({1-[(4-carbamimidoylfuran-2-yl)methyl]-1H-imidazo[1,2-b]pyrazol-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 1.30 (s, 3H), 1.32 (s, 3H), 2.95 (d, 1H, J=18Hz), 3.24 (d, 1H, J=18 Hz), 5.03 (d, 1H, J=4.8 Hz), 5.13 (d, 2H, J=4.8Hz), 5.29 (s, 2H), 5.62 (d, 1H, J=4.4 Hz), 6.26 (d, 1H, J=3.6 Hz), 6.85(s, 1H), 6.92 (s, 1H), 7.38 (s, 1H), 7.82 (s, 1H), 7.89 (d, 1H, J=3.6Hz), 8.13 (s, 1H). Seven protons were not observed in D₂O.

Mass: ES⁺ 697.25

Example 36 (Table 1, Compound 10)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-({1-[4-(2-carbamimidamidoethoxy)benzyl]-2,3-dihydro-1H-imidazo[1,2-b]pyrazol-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, DMSO-d₆): δ 1.30 (s, 3H), 1.32 (s, 3H), 3.03 (d, 1H,J=17.6 Hz), 3.25 (d, 1H, J=17.6 Hz), 3.43 (t, 2H, J=4.7 Hz), 3.79 (t,2H, J=8.2 Hz), 4.02-4.08 (m, 3H), 4.26 (m, 2H), 4.78 (d, 1H, J=15.3 Hz),4.87 (d, 1H, J=15.7 Hz), 5.03 (d, 1H, J=5.1 Hz), 5.61 (dd, 2H, J=5.05and 1.9 Hz), 6.84-6.86 (m, 3H), 7.17 (d, 2H, J=8.9 Hz), 7.78 (d, 1H,J=3.1 Hz), 8.18 (s, 1H). Eight protons were not observed in D₂O.

Mass: ES⁺ 768.31

Example 37 (Table 1, Compound 49)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-{[1-(4-carbamimidoyl-2-chloro-6-fluorobenzyl)-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 1.21 (s, 6H), 2.90 (d, 1H, J=17.6 Hz), 3.36 (d,1H, J=18.0 Hz), 5.05-5.09 (m, 2H), 5.32 (d, 1H, J=14.4 Hz), 5.59 (s,3H), 6.69 (s, 1H), 6.84 (d, 1H, J=3.2 Hz), 7.40 (d, 1H, J=9.6 Hz), 7.58(d, 2H, J=10.0 Hz), 7.87 (d, 1H, J=7.2 Hz), 8.28 (d, 1H, J=7.2 Hz), 9.00(s, 1H). Seven protons were not observed in D₂O.

Mass: ES⁺ 770.28

Example 38 (Table 1, Compound 27)(6R,7R)-7-{[(2Z)-2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-({1-[(4-carbamimidoylthiophen-2-yl)methyl]-1H-imidazo[1,2-b]pyrazol-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 1.28 (s, 3H), 1.30 (s, 3H), 2.90 (d, 1H, J=18.0Hz), 3.22 (d, 1H, J=18.0 Hz), 5.01 (d, 1H, J=4.7 Hz), 5.12 (s, 2H), 5.43(s, 2H), 5.62 (d, 1H, J=4.7 Hz), 6.17 (d, 1H, J=3.5 Hz), 7.38-7.40 (m,2H), 7.80-7.88 (m, 2H), 8.12 (s, 1H). Seven protons were not observed inD₂O.

Mass: ES⁺ 714.27

Example 39 (Table 1, Compound 51)(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-({1-[(4-carbamimidoylthiophen-2-yl)methyl]-1H-imidazo[1,2-b]pyrazol-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (D₂O): δ 2.90 (d, 1H, J=17.6 Hz), 3.15 (d, 1H, J=17.6 Hz), 3.78(s, 3H), 4.96 (d, 1H, J=4.8 Hz), 5.10 (d, 2H, J=3.6 Hz), 5.39 (s, 2H),5.63 (d, 1H, J=4.8 Hz), 6.15 (d, 1H, J=3.6 Hz), 7.37 (d, 2H, J=10.8 Hz),7.80 (d, 1H, J=2.4 Hz), 7.85 (d, 1H, J=2.4 Hz), 7.86 (s, 1H). Sixprotons were not observed in D₂O.

Mass: ES⁺ 676.10

Example 40 (Table 1, Compound 50)(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-({1-[(4-carbamimidoylthiophen-2-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (D₂O): δ 3.04 (d, 1H, J=17.6 Hz), 3.42 (d, 1H, J=18.0 Hz), 3.84(s, 3H), 5.10 (d, 1H, J=4.8 Hz), 5.21 (d, 1H, J=14.8 Hz), 5.34 (d, 1H,J=14.4 Hz), 5.70 (m, 3H), 6.98 (d, 1H, J=3.2 Hz), 7.35 (s, 1H), 7.74 (d,1H, J=3.2 Hz), 7.89 (d, 1H, J=6.8 Hz), 8.12 (s, 1H), 8.31 (d, 1H, J=2.4Hz), 9.08 (s, 1H). Six protons were not observed in D₂O.

Mass: ES⁺ 686.17

Example 41 (Table 1, Compound 52)(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-{[1-(4-carbamimidoyl-2-fluorobenzyl)-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 2.97 (d, 1H, J=18.0 Hz), 3.35 (d, 1H, J=17.6Hz), 3.77 (s, 3H), 5.03 (d, 1H, J=4.8 Hz), 5.14 (d, 1H, J=15.2 Hz), 5.26(d, 1H, J=14.0 Hz), 5.56 (s, 2H), 5.65 (d, 1H, J=4.8 Hz), 6.91 (d, 1H,J=3.6 Hz), 7.15 (t, 1H, J=8.0 Hz), 7.35 (d, 1H, J=7.6 Hz), 7.41 (d, 1H,J=10.4 Hz), 7.65 (d, 1H, J=3.2 Hz), 7.77 (d, 1H, J=7.2 Hz), 8.22 (d, 1H,J=8.4 Hz), 9.01 (s, 1H). Six protons were not observed in D₂O.

Mass: ES⁺ 698.16

Example 42 (Table 1, Compound 54)(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-8-oxo-3-{[1-(4-{N-[(3R)-piperidin-3-yl]carbamimidoyl}benzyl)-1H-pyrrol[3,2-c]pyridin-5-ium-5-yl]methyl}-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 1.56-1.92 (m, 2H), 1.88 (d, 1H, J=15.2 Hz),2.07 (d, 1H, J=10.4 Hz), 2.83-3.01 (m, 3H), 3.21 (d, 1H, J=12.8 Hz),3.32 (d, 1H, J=18.0 Hz), 3.47 (d, 1H, J=12.4 Hz), 3.74 (s, 3H),3.92-3.97 (m, 1H), 4.99 (d, 1H, J=4.8 Hz), 5.13 (d, 1H, J=14.8 Hz), 5.23(d, 1H, J=14.4 Hz), 5.51 (s, 2H), 5.60 (d, 1H, J=4.4 Hz), 6.90 (d, 1H,J=3.6 Hz), 7.17 (d, 2H, J=8.0 Hz), 7.47 (d, 2H, J=8.0 Hz), 7.63 (d, 1H,J=3.2 Hz), 7.66 (d, 1H, J=7.2 Hz), 8.16 (d, 1H, J=7.2 Hz), 9.00 (s, 1H).Six protons were not observed in D₂O.

Mass: ES⁺ 763.22

Example 43 (Table 1, Compound 53)(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-({-[(4-carbamimidoyl-1,3-thiazol-2-yl)methyl]-1H-imidazo[1,2-b]pyrazol-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 3.02 (d, 1H, J=16.4 Hz), 3.25 (d, 1H, J=18.4Hz), 3.83 (s, 3H), 5.04 (s, 1H), 5.11 (d, 1H, J=16.5 Hz), 5.20 (d, 1H,J=15.4 Hz), 5.67 (s, 3H), 6.34 (m, 1H), 7.51 (m, 1H), 7.87 (m, 1H), 7.95(m, 1H), 8.46 (s, 1H). Six protons were not observed in D₂O.

Mass: ES⁺ 677.13

Example 44 (Table 1, Compound 55)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-{[1-(4-carbamimidoyl-2-fluorobenzyl)-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 2.96 (d, 1H, J=17.6 Hz), 3.36 (d, 1H, J=18.0Hz), 3.75 (s, 3H), 5.04 (d, 1H, J=4.8 Hz), 5.12 (d, 1H, J=14.8 Hz), 5.26(d, 1H, J=14.8 Hz), 5.55 (s, 2H), 5.62 (d, 1H, J=4.8 Hz), 6.75 (s, 1H),6.90 (d, 1H, J=2.8 Hz), 7.11 (t, 1H, J=8.0 Hz), 7.33 (d, 1H, J=8.0 Hz),7.40 (d, 1H, J=10.8 Hz), 7.64 (d, 1H, J=3.2 Hz), 7.75 (d, 1H, J=6.8 Hz),8.21 (d, 1H, J=7.2 Hz), 9.00 (s, 1H). Six protons were not observed inD₂O.

Mass: ES⁺ 664.23

Example 45 (Table 1, Compound 58)(6R,7R)-7-{[(2Z)-2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-{[1-(4-carbamimidoyl-2-chloro-6-fluorobenzyl)-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

Step 1: 3-Chloro-5-fluoro-4-formylbenzonitrile

To a solution of 3-chloro-5-fluorobenzonitrile (1.8 g, 11.57 mmol) inanhydrous tetrahydrofuran (40 mL) at −78° C. was added lithiumdiisopropylamide (2M, 6.4 mL, 12.73 mmol). After stirring at sametemperature for 30 minutes was added dimethylformamide (1.02 g, 13.84mmol). The reaction mixture was stirred at −78° C. for an additional 15minutes, then was added acetic acid (2.7 mL) followed by water (40 mL)and the mixture was warmed to room temperature. After extraction withethyl acetate (60 mL), the organic phase was washed with 1M HClsolution, brine, dried over Na₂SO₄, filtered and evaporated to give3-chloro-5-fluoro-4-formylbenzonitrile (1.08 g, 51%) as a gummy solid.

¹H NMR (400 MHz, CDCl₃): δ 7.42 (m, 1H), 7.61 (d, 1H, J=2.8 Hz), 10.45(s, 1H).

Step 2: 3-Chloro-5-fluoro-4-(hydroxymethyl)benzonitrile

To a solution of 3-chloro-5-fluoro-4-formylbenzonitrile (from step 1,1.08 g, 5.88 mmol) in methanol (6 mL) was added sodium borohydride (0.25g, 6.61 mmol) at 0° C. After 15 minutes, the mixture was quenched withwater (1 mL) and concentrated to obtain a yellow oil residue. Dissolvedthe residue in ethyl acetate (35 mL), washed with water (30 mL) and theaqueous layer was extracted again with ethyl acetate (20 mL). Theextracts were combined, washed with brine, dried over Na₂SO₄, filteredand evaporated. The residue was purified by column chromatography(silica gel) eluting 1:1 ethyl acetate/hexanes as eluent to give3-chloro-5-fluoro-4-(hydroxymethyl)benzonitrile (0.65 g, 60%) as anorange thick oil.

¹H NMR (400 MHz, CDCl₃): δ 4.88 (s, 2H), 7.33 (m, 1H), 7.54 (d, 1H,J=1.2 Hz).

Step 3: 4-(Bromomethyl)-3-chloro-5-fluorobenzonitrile

To a solution of 3-chloro-5-fluoro-4-(hydroxymethyl)benzonitrile (fromstep 2, 0.65 g, 3.5 mmol) and carbon tetrabromide (1.25 g, 3.73 mmol) Idichloromethane (20 mL) was added triphenylphosphene (1.02 g, 2.73 mmol)slowly at 0° C. After stirring for 10 minutes at the same temperature,the solution was stirred overnight at room temperature. The solution wasconcentrated under reduced pressure and the residue was purified bycolumn chromatography (silica gel) eluting with 1:20 ethylacetate/hexanes as eluent to give4-(bromomethyl)-3-chloro-5-fluorobenzonitrile (0.72 g, 83%) as a whitesolid.

¹H NMR (400 MHz, CDCl₃): δ 4.59 (s, 2H), 7.32 (m, 1H), 7.54 (s, 1H,J=1.2 Hz).

Step 4:3-Chloro-5-fluoro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)benzonitrile

An ice-cold mixture of 5-azaindole (0.34 g, 2.88 mmol) inN,N-dimethylformamide (10 mL) was treated with sodium hydride (60% inmineral oil, 0.172 g, 4.32 mmol) in portions, then stirred at roomtemperature for 15 minutes. The mixture was cooled to 0° C., and thentreated with 4-(bromomethyl)-3-chloro-5-fluorobenzonitrile (from step 3,0.73 g, 2.93 mmol) in tetrahydrofuran (10 mL). The resulting mixture wasstirred at 0° C. for 1 hour then quenched with saturated ammoniumchloride solution. The mixture was extracted with ethyl acetate, and theextracts were washed with brine, dried (sodium sulphate), filtered andconcentrated in vacuo to brown oil, which was purified by columnchromatography (silica gel) eluting with 5:3:2 dichloromethane/ethylacetate/methanol as eluent to afford 3-chloro -5-fluoro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)benzonitrile (0.53 g, 65%) as awhite solid.

¹H NMR (400 MHz, CDCl₃): δ 5.49 (d, 2H, J=1.9 Hz), 6.62 (d, 1H, J=3.2Hz), 7.19 (d, 1H, J=2.8 Hz), 7.37-7.41 (m, 2H), 7.59 (s, 1H), 8.35 (d,1H, J=6.0 Hz), 8.91 (s, 1H).

Step 5: Ethyl3-chloro-5-fluoro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)benzenecarboximidatehydrochloride

Through a solution of3-chloro-5-fluoro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)benzonitrile(from step 4, 0.53 g, 1.86 mmol) in anhydrous ethanol (20 mL) in apressure vessel at 0° C. was bubbled a stream of anhydrous hydrogenchloride gas for 10 min. The reaction vessel was stoppered and stirredat room temperature for 18 h and the contents were transferred into aflask and evaporated under reduced pressure. The crude product wastriturated with ether, then dried under vacuum to provide ethyl3-chloro-5-fluoro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)benzenecarboximidatehydrochloride (0.64 g, 94%) as a white solid which was used in the nextstep without further purification.

Step 6:3-Chloro-5-fluoro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)benzenecarboximidamide

A pressure vessel containing a suspension of ethyl 3-chloro -5-fluoro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)benzenecarboximidatehydrochloride (from step 5, 0.64 g, 1.74 mol) in methanol (20 mL) wassaturated with ammonia gas and stoppered. The reaction mixture wasstirred at room temperature for 24 h, then excess ammonia was vented outand the contents were concentrated under reduced pressure. The residuewas triturated with hexanes and dried under vacuum to give3-chloro-5-fluoro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)benzenecarboximidamide(0.69 g, 130%) as a grey solid which was used in the next step withoutfurther purification.

Step 7: tert-Butyl{[3-chloro-5-fluoro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)phenyl]carbonoimidoyl}carbamate

A solution of3-chloro-5-fluoro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)benzenecarboximidamide(from step 6, 0.69 g. 1.74 mmol) in 1,4-dioxane (50 mL) was treated witha saturated sodium carbonate solution (25 mL) followed by di-tert-butyldicarbonate (2.51 g, 11.4 mmol) and stirred at room temperature for 40h. The reaction mixture was concentrated under reduced pressure toremove the volatiles and the remaining solution was dissolved in ethylacetate (60 mL), then washed with water (60 mL), brine solution (60 mL),dried and concentrated. The crude product was purified by silica gelcolumn chromatography using ethyl acetate: methanol:ammonium hydroxide(60:39:1) as eluent to afford tert-butyl{[3-chloro-5-fluoro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)phenyl]carbonoimidoyl}carbamate(0.3 g, 33%).

¹HNMR (400 MHz, CDCl₃): δ 1.52 (s, 9H), 5.43 (s, 2H), 6.56 (d, 1, J=3.2Hz), 7.18 (d, 1H, J=2.8 Hz), 7.37 (d, 1H, J=6.0 Hz), 7.58 (d, 1H, J=9.6Hz), 7.80 (s, 1H), 8.22 (d, 1H, J=5.6 Hz), 8.82 (s, 1H).

Step 8:5-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-Butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-{4-[N-(tert-butoxycarbonyl)carbamimidoyl]-2-chloro-6-fluorobenzyl}-1H-pyrrolo[3,2-c]pyridin-5-iumiodide

To a solution of tert-butyl{[3-chloro-5-fluoro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylmethyl)phenyl]carbonoimidoyl}carbamate(from step 7, 0.12 g, 0.30 mmol) in dimethylformamide (1 mL) was added(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-3-(iodomethyl)-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thionia-1-azabicyclo[4.2.0]oct-2-en-5-olate(0.24 g, 0.30 mmol) at 0° C. The reaction mixture was then degassedunder reduced pressure for 0.5 h, and stirred at room temperature for 16h.

Dimethyl formamide (2 mL) was added and cooled to −40° C., followed byadding KI (0.35 g, 2.1 mmol) and acetyl chloride (0.09 mL, 1.2 mmol).After stirring at 0° C. for 1 h, ice water and ethyl acetate (30 mL)were poured to the reaction solution, and then NaHSO₃ solution (20 mL)was added. The aqueous solution was extracted with ethyl acetate (30mL×2) and the organic layers were combined, washed with brine (3×50 mL),dried over Na₂SO₄, filtered and evaporated to give yellow solid (0.29g), which was used in the next step without further purification.

Step 9:(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-{[1-(4-carbamimidoyl-2-chloro-6-fluorobenzyl)-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

To a solution of5-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-{4-[N-(tert-butoxycarbonyl)carbamimidoyl]-2-chloro-6-fluorobenzyl}-1H-pyrrolo[3,2-c]pyridin-5-iumiodide (0.29 g) in dry dichloromethane (6 mL) at −40° C. was addedanisole (0.52 mL, 4.92 mmol) and then 2M AlCl₃ in CH₃NO₂ (2.46 mL, 4.92mmol). The liquid was stirred at 0° C. for 30 min. To the reactionmixture were added diisopropyl ether (10 mL) and water (0.5 mL), and theresultant was stirred to generate a precipitate. The supernatant wasremoved by decantation. To the insoluble matter adhering to the vesselwere added diluted aqueous hydrochloric acid solution (5 mL) andacetonitrile (10 mL). The resultant was stirred to dissolve the mattercompletely. Thereto was added HP20 resin (1.0 g), and stirred for 30min, and then filtered. The filtrate was concentrated and lyophilized togive a crude product which was purified by HPLC to obtain(6R,7R)-7-{[(2Z)-2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-{[1-(4-carbamimidoyl-2-chloro-6-fluorobenzyl)-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylateas formic acid salt (0.0135 g, 7.5%).

¹H NMR (400 MHz, D₂O): δ 2.94 (d, 1H, J=18.0 Hz), 3.33 (d, 1H, J=17.6Hz), 3.73 (s, 3H), 5.00 (d, 1H, J=5.2 Hz), 5.11 (d, 1H, J=14.4 Hz), 5.26(d, 1H, J=14.0 Hz), 5.58-5.62 (m, 3H), 6.84 (s, 1H), 7.39 (d, 1H, J=9.6Hz), 7.58 (s, 2H), 7.89 (d, 1H, J=7.2 Hz), 8.25 (d, 1H, J=6.4 Hz), 8.97(s, 1H). Six protons were not observed in D₂O.

Mass: ES⁺ 732.21

Example 46 (Table 1, Compound 56)(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-({1-[(4-carbamimidoylfuran-2-yl)methyl]-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 2.91 (d, 1H, J=18.0 Hz), 3.34 (d, 1H, J=18.0Hz), 3.77 (s, 3H), 5.03 (d, 1H, J=4.8 Hz), 5.15 (d, 1H, J=15.2 Hz), 5.26(d, 1H, J=14.0 Hz), 5.47 (s, 2H), 5.65 (d, 1H, J=4.8 Hz), 6.74 (s, 1H),6.88 (d, 1H, J=3.2 Hz), 7.64 (d, 1H, J=3.6 Hz), 7.86 (d, 1H, J=7.6 Hz),8.04 (s, 1H), 8.25 (d, 1H, J=4.0 Hz), 8.99 (s, 1H). Six protons were notobserved in D₂O.

Mass: ES⁺ 670.06

Example 47 (Table 1, Compound 65)(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-({1-[(4-carbamimidoylthiophen-2-yl)methyl]-1H-pyrrolo[2,3-c]pyridin-6-ium-6-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹HNMR (400 MHz, D₂O): δ 1.33 (s, 3H), 1.35 (s, 3H), 2.95 (d, 1H, J=18.0Hz), 3.38 (d, 1H, J=18.4 Hz), 5.07-5.11 (m, 2H), 5.39 (d, 1H, J=14.5Hz), 5.67-5.78 (m, 3H), 6.88 (d, 1H, J=2.8 Hz), 7.47 (s, 1H), 7.96 (d,1H, J=6.0 Hz), 8.12 (m, 3H), 9.10 (s, 1H). Seven protons were notobserved in D₂O.

Mass: ES⁺ 758.17

Example 48 (Table 1, Compound 66)(6R,7R)-7-{[(2Z)-2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-({1-[(4-carbamimidoylthiophen-2-yl)methyl]-1H-pyrrolo[2,3-c]pyridin-6-ium-6-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 1.37 (s, 3H), 1.39 (s, 3H), 2.97 (d, 1H, J=18.0Hz), 3.38 (d, 1H, J=17.6 Hz), 5.08-5.13 (m, 2H), 5.37 (d, 1H, J=14.4Hz), 5.69-5.80 (m, 3H), 6.85 (d, 1H, J=2.8 Hz), 7.46 (s, 1H), 7.94 (d,1H, J=6.8 Hz), 8.09-8.16 (m, 3H), 9.08 (s, 1H). Seven protons were notobserved in D₂O.

Mass: ES⁺ 725.16

Example 49 (Table 1, Compound 67)(6R,7R)-7-{[(2Z)-2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-(methoxyimino)acetyl]amino}-3-({1-[(4-carbamimidoylthiophen-2-yl)methyl]-1H-pyrrolo[2,3-c]pyridin-6-ium-6-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 2.96 (d, 1H, J=17.6 Hz), 3.38 (d, 1H, J=17.6Hz), 3.95 (s, 3H), 5.06 (d, 1H, J=4.8 Hz), 5.12 (d, 1H, J=14.8 Hz), 5.31(d, 1H, J=14.4 Hz), 5.53 (d, 1H, J=4.8 Hz), 5.72 (m, 2H), 6.88 (d, 1H,J=3.2 Hz), 7.50 (s, 1H), 7.95 (d, 1H, J=6.4 Hz), 8.11-8.30 (m, 3H), 8.99(s, 1H). Six protons were not observed in D₂O.

Mass: ES⁺ 653.19

Example 50 (Table 1, Compound 68)(6R,7R)-7-{[(2Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-({1-[(4-carbamimidoylthiophen-2-yl)methyl]-1H-pyrrolo[3,2-b]pyridin-4-ium-4-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 1.40 (s, 6H), 3.03 (d, 1H, J=17.6 Hz), 3.24 (d,1H, J=17.6 Hz), 5.06 (d, 1H, J=4.8 Hz), 5.42 (d, 1H, J=15.2 Hz), 5.58(d, 1H, J=15.2 Hz), 5.71 (d, 1H, J=4.8 Hz), 5.76 (s, 2H), 6.95 (d, 1H,J=3.2 Hz), 7.34 (s, 1H), 7.54-7.58 (m, 1H), 8.08 (d, 1H, J=3.2 Hz), 8.12(s, 1H), 8.48-8.53 (m, 2H). Seven protons were not observed in D₂O.

Mass: ES⁺ 725.13

Example 51 (Table 1, Compound 71)(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-{[1-(4-carbamimidoyl-2-chloro-6-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridin-4-ium-4-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

Step 1:3-Chloro-5-fluoro-4-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)benzonitrile

An ice-cold mixture of 4-azaindole (0.47 g, 3.98 mmol) inN,N-dimethylformamide (10 mL) was treated with sodium hydride (60% inmineral oil, 0.23 g, 6.0 mmol) in portions, then stirred at roomtemperature for 15 minutes. The mixture was cooled to 0° C., thentreated with 4-(bromomethyl)-3-chloro-5-fluorobenzonitrile (1.00 g, 4.00mmol) in tetrahydrofuran (10 mL). The resulting mixture was stirred at0° C. for 1 hour then quenched with saturated ammonium chloridesolution. The mixture was extracted with ethyl acetate and the extractswere washed with brine, dried (sodium sulphate), filtered andconcentrated in vacuo to brown oil, which was purified by columnchromatography (silica gel) eluting with 5:3:2 dichloromethane/ethylacetate/methanol as eluent to afford3-chloro-5-fluoro-4-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)benzonitrile(0.62 g, 54%) as brown solid.

¹HNMR (400 MHz, CDCl₃): δ 5.49 (d, 2H, J=1.9 Hz), 6.72 (d, 1H, J=3.4Hz), 7.14 (dd, 1H, J=8.2, 4.7 Hz), 7.37 (d, 1H, J=8.7 Hz), 7.41 (d, 1H,J=3.4 Hz), 7.58 (br s, 1H,) 7.78 (d, 1H, J=8.4 Hz), 8.47 (d, 1H, J=4.7Hz).

Step 2: Ethyl3-chloro-5-fluoro-4-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)benzenecarboximidatehydrochloride

Anhydrous hydrochloric acid was bubbled into an ice-cold brownsuspension of3-chloro-5-fluoro-4-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)benzonitrile(0.65 g, 2.23 mmol) in anhydrous ethanol (30 mL) for 10 minutes. Themixture was sealed and stirred at room temperature overnight. Themixture was concentrated in vacuo to afford ethyl3-chloro-5-fluoro-4-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)benzenecarboximidatehydrochloride (0.83 g) as a brown solid, which was used in the next stepwithout further purification.

¹HNMR (400 MHz, CD₃OD): δ 1.58 (t, 3H, J=7.2H), 4.59 (q, 2H, J=7.0 Hz),6.09 (s, 2H), 7.15 (d, 1H, J=3.2 Hz), 7.92-8.04 (m, 2H), 8.16 (s, 1H),8.34 (d, 1H, J=2.9 Hz), 8.83 (d, 1H, J=5.6 Hz), 9.03 (d, 1H, J=8.2 Hz).

Step 3:3-Chloro-5-fluoro-4-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)benzenecarboximidamide

Anhydrous ammonia was bubbled into an ice-cold solution of3-chloro-5-fluoro-4-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)benzenecarboximidatehydrochloride (0.83 g, 2.23 mmol) in anhydrous ethanol (30 mL) for 10minutes. The mixture was sealed and stirred at room temperatureovernight. The mixture was concentrated in vacuo to afford3-chloro-5-fluoro-4-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)benzenecarboximidamideas a brown solid (0.72 g), which was used in the next step withoutfurther purification.

¹H NMR (400 MHz, CD₃OD): δ 5.59 (s, 2H), 6.62 (br s, 1H), 7.22 (br s,1H), 7.54-7.60 (m, 2H), 7.64-7.69 (m, 1H), 7.82-7.87 (m, 1H), 8.23-8.43(br s, 1H).

Step 4: tert-Butyl{[3-chloro-5-fluoro-4-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)phenyl]carbonoimidoyl}carbamate

An ice-cold solution of3-chloro-5-fluoro-4-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)benzenecarboximidamide(0.72 g, 2.38 mmol) in dioxane (40 mL) and saturated sodium carbonatesolution (20 mL) was treated with di-tert-butyl dicarbonate (2.08 g,9.53 mmol). The mixture was stirred at room temperature overnight, thenconcentrated in vacuo. The residue was diluted with ethyl acetate andwashed with water and brine, then dried (sodium sulphate), filtered andconcentrated to brown solid, which was purified by column chromatography(silica gel) eluting with 2-4% methanol in dichloromethane to affordtert-butyl{[3-chloro-5-fluoro-4-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)phenyl]carbonoimidoyl}carbamate(0.20 g, 21%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃): δ 1.55 (s, 9H), 5.47 (d, 2H, J=1.8 Hz), 6.60(d, 1H, J=3.2 Hz), 7.19 (d, 1H, J=3.1 Hz), 7.41 (d, 1H, J=6.0 Hz),7.55-7.60 (m, 1H), 7.78 (s, 1H), 8.31 (d, 1H, J=6.0 Hz), 8.88 (s, 1H).

Step 5:4-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-Butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-{4-[N-(tert-butoxycarbonyl)carbamimidoyl]-2-chloro-6-fluorobenzyl}-1H-pyrrolo[3,2-b]pyridin-4-iumiodide

An ice-cold mixture of tert-butyl{[3-chloro-5-fluoro-4-(1H-pyrrolo[3,2-b]pyridin-1-ylmethyl)phenyl]carbonoimidoyl}carbamate(0.20 g, 0.50 mmol) in anhydrous N,N-dimethylformamide (2.0 mL) wasdegassed under reduced pressure for 5 minutes, then treated with4-methoxybenzyl(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate(0.34 g, 0.50 mmol). The resulting mixture was degassed for 30 minutes,and treated with sodium iodide (0.15 g, 1.00 mmol). The mixture wasstirred at room temperature overnight, cooled to 0° C. and quenched witha 5% aqueous solution of sodium chloride and sodium thiosulfate to givean orange suspension. The solid was filtered, washed with water anddried in vacuo to afford4-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-{4-[N-(tert-butoxycarbonyl)carbamimidoyl]-2-chloro-6-fluorobenzyl}-1H-pyrrolo[3,2-b]pyridin-4-iumiodide, which was used in the next step without further purification.

Step 6:(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-{[1-(4-carbamimidoyl-2-chloro-6-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridin-4-ium-4-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

A solution of4-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-{4-[N-(tert-butoxycarbonyl)carbamimidoyl]-2-chloro-6-fluorobenzyl}-1H-pyrrolo[3,2-b]pyridin-4-iumiodide (0.50 mmol) in dichloromethane (2.5 mL) and anisole (0.85 mL,7.82 mmol) was cooled to 0° C., then treated with trifluoroacetic acid(2.5 mL, 32.6 mmol). The resulting brown solution was stirred at 0° C.for 10 minutes, then at room temperature for 2 hours. The mixture wasconcentrated in vacuo to a brown residue, which was washed with diethylether and the brown solid was purified by preparative HPLC (0.1% formicacid in water/acetonitrile) to afford(6R,7R)-7-{[(2Z)-2-(2-amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-{[1-(4-carbamimidoyl-2-chloro-6-fluorobenzyl)-1H-pyrrolo[3,2-b]pyridin-4-ium-4-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate(0.050 g, 14% over 2 steps) as formic acid salt.

¹H NMR (400 MHz, D₂O): δ 3.18 (d, 1H, J=17.9 Hz), 3.32 (d, 1H, J=17.9Hz), 3.95 (s, 3H) 5.12 (d, 1H, J=5.0 Hz), 5.50 (d, 1H, J=14.7 Hz), 5.71(d, 1H, J=15.0 Hz), 5.80 (d, 1H, J=4.7 Hz), 5.85 (s, 2H), 7.01 (d, 1H,J=3.5 Hz), 7.62 (dd, 1H, J=9.7, 1.7 Hz), 7.70 (dd, 1H, J=8.2, 6.2 Hz),7.80 (s, 1H), 8.15 (d, 1H, J=3.2 Hz), 8.62 (d, 1H, J=6.2 Hz), 8.69 (d,1H, J=8.5 Hz).

Six protons were not observed in D₂O.

Mass: ES⁺ 732.15.

Example 52 (Table 1, Compound 69)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-{[1-(4-carbamimidoyl-2-chloro-6-fluorobenzyl)-1H-pyrrolo[3,2-c]pyridin-5-ium-5-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 3.14 (d, 1H, J=17.9 Hz), 3.58 (d, 1H, J=17.9Hz), 3.93 (s, 3H), 5.22 (d, 1H, J=5.0 Hz), 5.29 (d, 1H, J=14.7 Hz), 5.48(d, 1H, J=14.4 Hz), 5.74-5.79 (m, 3H), 6.82 (s, 1H), 7.02 (d, 1H, J=3.2Hz), 7.60 (dd, 1H, J=9.7, 1.5 Hz), 7.73-7.81 (m, 2H), 8.06 (d, 1H, J=7.3Hz), 8.44 (d, 1H, J=7.0 Hz), 9.17 (s, 1H). Six protons were not observedin D₂O.

Mass: ES⁺ 698.19.

Example 53 (Table 1, Compound 70)(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-{[1-(4-carbamimidoyl-2-chloro-6-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridin-6-ium-6-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylateformic acid salt

Step 1:3-Chloro-5-fluoro-4-(1H-pyrrolo[2,3-c]pyridin-1-ylmethyl)benzonitrile

An ice-cold mixture of 6-azaindole (0.98 g, 7.96 mmol) inN,N-dimethylformamide (10 mL) was treated with sodium hydride (60% inmineral oil, 0.46 g, 12.0 mmol) in portions, then stirred at roomtemperature for 15 minutes. The mixture was cooled to 0° C., thentreated with 4-(bromomethyl)-3-chloro-5-fluorobenzonitrile (2.00 g, 8.05mmol) in tetrahydrofuran (10 mL). The resulting mixture was stirred at0° C. for 1 hour then quenched with saturated ammonium chloridesolution. The mixture was extracted with ethyl acetate, and the extractswere washed with brine, dried (sodium sulphate), filtered andconcentrated in vacuo to brown oil, which was purified by columnchromatography (silica gel) eluting with 5:3:2 dichloromethane/ethylacetate/methanol as eluent to afford3-chloro-5-fluoro-4-(1H-pyrrolo[2,3-c]pyridin-1-ylmethyl)benzonitrile(1.14 g, 50%) as a brown solid.

¹HNMR (400 MHz, CDCl₃): δ 5.59 (d, 2H, J=1.9 Hz), 6.54 (dd, 1H) 7.31(dd, 1H, J=3.15, 1.25 Hz), 7.38 (dd, 1H, J=8.7, 1.6 Hz), 7.51 (dd, 1H,J=5.4, 1.0 Hz), 7.59 (t, 1H, J=1.4 Hz), 8.27 (d, 1H, J=5.4 Hz), 8.92 (s,1H).

Step 2: Ethyl3-chloro-5-fluoro-4-(1H-pyrrolo[2,3-c]pyridin-1-ylmethyl)benzenecarboximidatehydrochloride

Anhydrous hydrochloric acid was bubbled into an ice-cold brownsuspension of3-chloro-5-fluoro-4-(1H-pyrrolo[2,3-c]pyridin-1-ylmethyl)benzonitrile(1.14 g, 3.99 mmol) in anhydrous ethanol (30 mL) for 10 minutes. Themixture 5 was sealed and stirred at room temperature overnight. Themixture was concentrated in vacuo to afford ethyl3-chloro-5-fluoro-4-(1H-pyrrolo[2,3-c]pyridin-1-ylmethyl)benzenecarboximidatehydrochloride (1.16 g) as a brown solid, which was used in the next stepwithout further purification.

Step 3:3-Chloro-5-fluoro-4-(1H-pyrrolo[2,3-c]pyridin-1-ylmethyl)benzenecarboximidamide

Anhydrous ammonia was bubbled into an ice-cold solution of ethyl3-chloro-5-fluoro-4-(1H-pyrrolo[2,3-c]pyridin-1-ylmethyl)benzenecarboximidatehydrochloride (1.6 g, 4.34 mmol) in anhydrous ethanol (30 mL) for 10minutes. The mixture was sealed and stirred at room temperatureovernight. The mixture was concentrated in vacuo to afford3-chloro-5-fluoro-4-(1H-pyrrolo[2,3-c]pyridin-1-ylmethyl)benzenecarboximidamideas a brown solid (0.59 g), which was used in the next step withoutfurther purification.

¹H NMR (400 MHz, CD₃OD): δ 5.80 (s, 2H), 6.64-6.71 (m, 1H), 7.55-7.74(m, 3H), 7.84-7.91 (m, 1H), 8.12 (s, 1H), 8.92 (s, 1H).

Step 4: tert-Butyl{[3-chloro-5-fluoro-4-(1H-pyrrolo[2,3-c]pyridin-1-ylmethyl)phenyl]carbonoimidoyl}carbamate

An ice-cold solution of3-chloro-5-fluoro-4-(1H-pyrrolo[2,3-c]pyridin-1-ylmethyl)benzenecarboximidamide(0.59 g, 1.95 mmol) in dioxane (40 mL) and saturated sodium carbonatesolution (20 mL) was treated with di-tert-butyl dicarbonate (1.70 g,7.78 mmol). The mixture was stirred at room temperature overnight andconcentrated in vacuo. The residue was diluted with ethyl acetate,washed with water and brine, then dried (sodium sulphate), filtered andconcentrated to a brown solid. The solid was purified by columnchromatography (silica gel) eluting with 2-4% methanol indichloromethane to afford tert-butyl{[3-chloro-5-fluoro-4-(1H-pyrrolo[2,3-c]pyridin-1-ylmethyl)phenyl]carbonoimidoyl}carbamate(0.64 g, 82%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃): δ 1.55 (s, 9H), 5.53 (d, 2H, J=1.5 Hz), 6.49(d, 1H, J=3.2 Hz), 7.30 (d, 1H, J=3.2 Hz), 7.48 (d, 1H, J=5.4 Hz),7.57-7.63 (m, 1H), 7.81 (s, 1H), 8.21 (d, 1H, J=5.4 Hz), 8.91 (s, 1H).

Step 5:6-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-Butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-{4-[N-(tert-butoxycarbonyl)carbamimidoyl]-2-chloro-6-fluorobenzyl}-1H-pyrrolo[2,3-c]pyridin-6-iumiodide

An ice-cold mixture of tert-butyl{[3-chloro-5-fluoro-4-(1H-pyrrolo[2,3-c]pyridin-1-ylmethyl)phenyl]carbonoimidoyl}carbamate(0.20 g, 0.50 mmol) in anhydrous N,N-dimethylformamide (2.0 mL) wasdegassed under reduced pressure for 5 minutes, then treated with4-methoxybenzyl(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate(0.34 g, 0.50 mmol). The resulting mixture was degassed for 30 minutes,then treated with sodium iodide (0.15 g, 1.00 mmol). The mixture wasstirred at room temperature overnight, then cooled to 0° C. and quenchedwith a 5% aqueous solution of sodium chloride and sodium thiosulfate togive an orange suspension. The solid was filtered, washed with water anddried in vacuo to afford6-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-{4-[N-(tert-butoxycarbonyl)carbamimidoyl]-2-chloro-6-fluorobenzyl}-1H-pyrrolo[2,3-c]pyridin-6-iumiodide, which was used in the next step without further purification.

Step 6:(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-{[1-(4-carbamimidoyl-2-chloro-6-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridin-6-ium-6-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

A solution of6-{[(6R,7R)-7-{[(2Z)-2-{2-[(tert-butoxycarbonyl)amino]-5-chloro-1,3-thiazol-4-yl}-2-(methoxyimino)acetyl]amino}-2-{[(4-methoxybenzyl)oxy]carbonyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl}-1-{4-[N-(tert-butoxycarbonyl)carbamimidoyl]-2-chloro-6-fluorobenzyl}-1H-pyrrolo[2,3-c]pyridin-6-iumiodide (0.50 mmol) in dichloromethane (2.5 mL) and anisole (0.85 mL,7.82 mmol) was cooled to 0° C., then treated with trifluoroacetic acid(2.5 mL, 32.6 mmol). The resulting brown solution was stirred at 0° C.for 10 minutes, then at room temperature for 2 hours. The mixture wasconcentrated in vacuo to a brown residue, which was washed with diethylether to afford the crude product as brown solid. The solid was purifiedby preparative HPLC (0.1% formic acid in water/acetonitrile) to afford(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-{[1-(4-carbamimidoyl-2-chloro-6-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridin-6-ium-6-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate(0.025 g, 7% over 2 steps) as formic acid salt.

¹H NMR (400 MHz, D₂O): δ 3.18 (d, 1H, J=18.2 Hz), 3.59 (d, 1H, J=17.9Hz), 3.95 (s, 3H), 5.21-5.32 (m, 2H), 5.56 (d, 1H, J=14.1 Hz), 5.79-5.90(m, 3H), 6.96 (d, 1H, J=3.2 Hz), 7.62 (dd, 1H, J=9.5, 1.60 Hz), 7.78 (s,1H), 8.05 (d, 1H, J=6.8 Hz), 8.20 (d, 1H, J=3.2 Hz), 8.24 (d, 1H, J=6.8Hz), 9.09 (s, 1H). Six protons were not observed in D₂O.

Mass: ES⁺ 732.04.

Example 54 (Table 1, Compound 72)(6R,7R)-7-{[(2Z)-2-(2-Amino-5-chloro-1,3-thiazol-4-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-{[1-(4-carbamimidoyl-2-chloro-6-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridin-6-ium-6-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 1.46 (s, 3H), 1.47 (s, 3H), 3.16 (d, 1H, J=18.2Hz), 3.61 (d, 1H, J=17.9 Hz), 5.21 (d, 1H, J=14.1 Hz), 5.28 (d, 1H,J=5.0 Hz), 5.61 (d, 1H, J=14.4 Hz), 5.79-5.91 (m, 3H), 6.95 (d, 1H,J=2.6 Hz), 7.61 (d, 1H, J=10.0 Hz), 7.78 (s, 1H), 8.04 (d, 1H, J=6.8Hz), 8.21 (d, 1H, J=2.4 Hz), 8.24 (d, 1H, J=6.8 Hz), 9.13 (s, 1H). Sixprotons were not observed in D₂O.

Mass: ES⁺ 804.13

Example 55 (Table 1, Compound 73)(6R,7R)-7-{[(2Z)-2-(2-Amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetyl]amino}-3-{[1-(4-carbamimidoyl-2-chloro-6-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridin-6-ium-6-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 3.16 (d, 1H, J=17.9 Hz), 3.63 (d, 1H, J=17.9Hz), 3.94 (s, 3H), 5.19-5.33 (m, 2H), 5.58 (d, 1H, J=14.4 Hz), 5.78 (d,1H, J=5.0 Hz), 5.82 (d, 2H, J=5.0 Hz), 6.95 (s, 2H), 7.60 (d, 1H, J=9.7Hz), 7.73 (s, 1H), 8.04 (d, 1H, J=6.8 Hz), 8.16 (d, 1H, J=2.9 Hz), 8.24(d, 1H, J=7.34 Hz), 9.13 (s, 1H). Six protons were not observed in D₂O.

Mass: ES⁺ 698.13.

Example 56 (Table 1, Compound 74)(6R,7R)-7-{[(2Z)-2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-{[(2-carboxypropan-2-yl)oxy]imino}acetyl]amino}-3-{[1-(4-carbamimidoyl-2-chloro-6-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridin-6-ium-6-yl]methyl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

¹H NMR (400 MHz, D₂O): δ 1.46 (s, 6H), 3.15 (d, 1H, J=17.9 Hz), 3.61 (d,1H, J=18.2 Hz), 5.20 (d, 1H, J=14.4 Hz), 5.28 (d, 1H, J=5.0 Hz), 5.61(d, 1H, J=14.4 Hz), 5.80-5.88 (m, 3H), 6.95 (d, 1H, J=3.23 Hz), 7.60(dd, 1H, J=9.4, 1.8 Hz), 7.76 (s, 1H), 8.03 (d, 1H, J=6.8 Hz), 8.20 (d,1H, J=2.9 Hz), 8.24 (dd, 1H, J=6.8, 1.2 Hz), 9.13 (s, 1H). Six protonswere not observed in D₂O.

Mass: ES⁺ 771.18

Antibacterial Activity and Synergistic Activity:

Without limitation, the present cephem compounds alone, or incombination with one or more β-lactamase inhibitors, may provideimproved antibacterial efficacy, particularly in antibiotic-resistantbacterial strains. It is believed that the present compounds may bestructurally different from known compounds and, as a result, may bemore basic in nature. It is an advantage that the present compounds mayextend the spectrum of effective bacterial compounds, particularlyagainst previously-resistant bacteria (e.g. ESKAPE organisms), and/orgram negative bacteria, without significant side effects. In a preferredembodiment, the present cephem compound may comprise reference compoundceftazidime, which may be used alone, or in combination with one or moreβ-lactamase inhibitors, such as NXL-104. As shown, the foregoingcomposition was tested for minimum inhibitory concentration (MIC, μg/mL)against bacteria listed in Tables 2-3.

TABLE 2 MIC values of selected compounds alone and in combination withNXL-104 against G(+) and G(−) isolates Resistance CAZ: Ex-1: EX-2: EX-5:Ex-6: Isolate Mechanism CAZ NXL104 Ex-1 NXL104 EX-2 NXL104 Ex-5 NXL104Ex-6 NXL104 S. aureus 3132 MSSA 8.00 8.00 2.00 2.00 2.00 2.00 2.00 4.004.00 S. aureus 3136 MSSA 8.00 8.00 2.00 2.00 2.00 2.00 2.00 2.00 4.004.00 S. aureus3137 MSSA 32.00 32.00 8.00 8.00 32.00 32.00 32.00 4.0032.00 8.00 S. aureus 3144 MSSA 16.00 16.00 4.00 4.00 4.00 4.00 4.00 4.008.00 8.00 S. aureus 3147 MSSA 8.00 8.00 2.00 2.00 2.00 2.00 2.00 2.004.00 4.00 S. pneumoniae ATCC Pen R 16.00 8.00 2.00 2.00 8.00 8.00 2.002.00 2.00 2.00 700673 S. pneumoniae ATCC Pen S 0.12 0.12 ≤0.06 ≤0.06≤0.06 ≤0.06 ≤0.06 ≤0.06 ≤0.06 ≤0.06 6301 S. pneumoniae 2389 Pen R 16.0016.00 4.00 4.00 8.00 8.00 2.00 1.00 2.00 2.00 S. pneumoniae 2392 Pen R16.00 16.00 2.00 2.00 8.00 8.00 2.00 1.00 2.00 2.00 S. pneumoniae 2492Pen R 8.00 8.00 2.00 2.00 8.00 8.00 2.00 2.00 2.00 2.00 S. pneumoniae2493 Pen R 16.00 16.00 4.00 4.00 8.00 8.00 2.00 2.00 2.00 2.00 S.pneumoniae 2403 Pen S 0.12 0.12 ≤0.06 ≤0.06 ≤0.06 ≤0.06 ≤0.06 ≤0.06≤0.06 ≤0.06 S. pneumoniae 2404 Pen S 32.00 32.00 0.25 0.12 0.25 0.25≤0.06 ≤0.06 ≤0.06 ≤0.06 S. pneumoniae 2405 Pen S 0.25 0.25 ≤0.06 ≤0.060.12 ≤0.06 ≤0.06 ≤0.06 ≤0.06 ≤0.06 S. pneumoniae 2406 Pen S 0.12 0.12≤0.06 ≤0.06 ≤0.06 ≤0.06 ≤0.06 ≤0.06 ≤0.06 ≤0.06 S. pneumoniae 2407 Pen S4.00 32.00 0.12 0.12 0.12 0.12 ≤0.06 ≤0.06 ≤0.06 ≤0.06 E. cloacae 2704P99 16.00 4.00 16.00 16.00 4.00 1.00 16.00 2.00 32.00 1.00 E. cloacae551 Caz R, IMP S 16.00 4.00 32.00 1.00 8.00 1.00 32.00 1.00 16.00 1.00E. cloacae 552 Caz S, IMP S 0.50 0.25 0.12 0.12 0.12 0.12 0.12 ≤0.060.12 0.25 E. cloacae 566 Caz R, IMP S >32 2.00 4.00 0.50 0.50 0.25 2.000.50 4.00 0.50 E. cloacae596 Caz R, IMP S 4.00 1.00 4.00 0.50 0.50 0.258.00 0.25 8.00 0.50 E. cloacae 2044 Caz S, IMP S 1.00 0.25 0.25 0.120.25 0.12 0.50 0.12 0.12 ≤0.06 C. freundii 15 Caz R, IMP S 8.00 2.0016.00 0.50 4.00 0.50 16.00 0.50 8.00 0.50 C. freundii 579 Caz R, IMP S4.00 2.00 4.00 0.25 2.00 0.50 4.00 0.25 2.00 0.25 C. freundii 580 Caz R,IMP S 8.00 2.00 16.00 0.50 4.00 0.50 8.00 0.25 4.00 0.25 C. freundii2003 Caz R, IMP S 4.00 1.00 8.00 0.25 2.00 0.50 8.00 0.25 4.00 0.50 C.freundii 2487 Caz R, IMP S 16.00 8.00 32.00 1.00 8.00 1.00 32.00 1.008.00 1.00 K. pneumoniae 4104 KPC-3, TEM-1 32.00 8.00 16.00 2.00 8.002.00 32.00 2.00 32.00 2.00 K. pneumoniae 4105 KPC-3, TEM-1, 32.00 4.0016.00 2.00 32.00 2.00 32.00 1.00 32.00 1.00 SHV-11 K. pneumoniae 4106KPC-3, TEM-1, 16.00 4.00 8.00 1.00 8.00 2.00 16.00 1.00 16.00 1.00SHV-12, SHV-141 K. pneumoniae 4107 KPC-2, TEM-1, 32.00 8.00 16.00 2.0016.00 4.00 32.00 2.00 32.00 2.00 SHV-11 K. pneumoniae 4108 KPC-3,TEM-166, 16.00 4.00 4.00 0.50 4.00 1.00 8.00 0.50 16.00 0.50 SHV-12,SHV-141 K. pneumoniae 4109 SHV-1, SHV-12 2.00 0.50 2.00 0.12 0.50 0.128.00 0.12 8.00 0.12 M. morganii 2409 High level cephase 16.00 4.00 8.001.00 8.00 1.00 16.00 0.50 16.00 1.00 (ACC 43: 769-776, 1999),β-Lactamase producing K. pneumoniae 2689 KPC-2 32.00 4.00 8.00 2.00 8.002.00 8.00 1.00 16.00 1.00 E. coli 2671 VIM-19 32.00 32.00 16.00 16.004.00 4.00 16.00 16.00 32.00 32.00 K. pneumoniae 2697 IMP-4 8.00 2.004.00 0.50 4.00 1.00 16.00 0.50 16.00 0.50 E. coli 4080 TEM-10 16.00 4.004.00 1.00 8.00 1.00 16.00 0.50 16.00 0.50 E. coli 4098 CTX-M-15, TEM-12.00 0.50 4.00 0.25 1.00 0.25 >32 0.12 32.00 0.12 E. coli 4101 CTX-M-14,TEM-1 0.50 0.25 0.50 0.12 0.50 0.12 0.50 0.12 0.50 ≤0.06 E. coli 4102CTX-M-14 1.00 0.25 1.00 0.12 1.00 0.12 1.00 ≤0.06 2.00 0.12 E. coli 102TEM-1 0.12 0.12 ≤0.06 ≤0.06 ≤0.06 ≤0.06 ≤0.06 ≤0.06 ≤0.06 ≤0.06 K.baumanii 2579 OXA-25 >32 >32 32.00 8.00 >32 32.00 >32 8.00 >32 16.00 K.baumanii 4091 OXA-23 >32 16.00 16.00 4.00 8.00 2.00 8.00 2.00 16.00 4.00K. baumanii 4094 OXA-51 >32 32.00 16.00 32.00 32.00 8.00 16.00 4.0016.00 8.00 K. baumanii 4095 OXA-48 0.50 0.50 0.50 0.25 0.25 0.25 0.250.25 0.12 0.25 E. coli 2668 OXA-48 1.00 0.50 1.00 0.12 0.50 0.25 1.00≤0.06 0.50 0.12 P. aeruginosa 2573 OXA-10 (Class D) 8.00 8.00 4.00 2.002.00 4.00 4.00 4.00 2.00 2.00

TABLE 3 MIC values of selected compounds alone and in combination withNXL-104 against KPC-producing organisms Resistance CAZ: Ex-1: Ex-12:Ex-4: Isolate Mechanism CAZ NXL104 Ex-1 NXL104 Ex-12 NXL104 Ex-4 NXL104E. cloacae KPC-2 >32 2 32 1 32 1 4 0.5 2689 E. cloacae VIM-1,KPC- >32 >32 >32 >32 >32 >32 >32 >32 2705 3type E. cloacae VIM-1,KPC-3 >32 32 >32 32 >32 >32 >32 32 2706 E. cloacae KPC-3, VIM-1 >32 8 324 32 4 8 4 2709 E. cloacae KPC-3, VIM-1 >32 >32 >32 >32 >32 >32 >32 >322710 E. coli 2666 KPC-2 >32 4 32 1 16 1 32 2 E. coli 4103 KPC-2,TEM- >32 16 >32 4 >32 4 >32 8 1, CMY-type K. pneumoniae KPC-2 >32 4 16 116 1 16 1 2689 K. pneumoniae KPC-2 >32 4 32 1 8 1 16 2 2690 K.pneumoniae KPC-3, VIM-1 >32 2 4 0.25 4 0.5 8 1 2711 K. pneumoniae KPC-3,VIM-1 >32 16 >32 4 >32 4 >32 4 2712 K. pneumoniae KPC-3, VIM-1 >32 8 >321 >32 2 >32 2 2713 K. pneumoniae KPC-3 >32 8 >32 4 >32 2 >32 4 4088 K.pneumoniae KPC-3, TEM-1 >32 2 32 1 16 1 16 1 4104 K. pneumoniae KPC-3,TEM- >32 4 32 2 32 2 >32 2 4105 1, SHV-11 K. pneumoniae KPC-3, TEM- >328 32 2 32 2 32 4 4106 1, SHV-12, SHV-141 K. pneumoniae KPC-2, TEM- >32 432 1 16 1 32 2 4107 1, SHV-11 K. pneumoniae KPC-3, TEM- >32 4 32 2 321 >32 2 4108 166, SHV- 12, SHV-141 P. aeruginosa KPC-2 >32 16 >32 8 3232 32 8 2686 Ex-14: Ex-2: Ex-5: Ex-6: Isolate Ex-14 NXL104 Ex-2 NXL104Ex-5 NXL104 Ex-6 NXL104 E. cloacae 16 0.5 8 0.5 16 0.5 16 1 2689 E.cloacae >32 >32 >32 >32 >32 >32 >32 >32 2705 E. cloacae >32 32 >3232 >32 32 >32 32 2706 E. cloacae 32 4 16 4 32 4 32 4 2709 E.cloacae >32 >32 >32 >32 >32 >32 >32 >32 2710 E. coli 2666 32 1 32 2 16 116 1 E. coli 4103 >32 8 >32 8 >32 4 >32 4 K. pneumoniae 32 1 32 2 8 1 161 2689 K. pneumoniae 32 1 32 2 8 .5 16 1 2690 K. pneumoniae 4 0.5 4 0.52 0.25 4 0.5 2711 K. pneumoniae >32 4 >32 4 >32 4 >32 4 2712 K.pneumoniae >32 2 >32 2 >32 2 >32 2 2713 K. pneumoniae >32 4 >32 4 322 >32 2 4088 K. pneumoniae 32 1 32 2 16 0.5 32 0.5 4104 K.pneumoniae >32 2 >32 2 32 1 32 2 4105 K. pneumoniae >32 4 >32 4 32 2 322 4106 K. pneumoniae 16 2 >32 2 16 1 16 1 4107 K. pneumoniae >32 2 >32 232 1 32 1 4108 P. aeruginosa >32 16 >32 16 32 8 32 8 2686

We claim:
 1. A compound of formula (I) or a pharmaceutically acceptablesalt thereof:

wherein in the formula (I), (i) A is define by the formula (Ia):

Wherewhere X is N, C(H), C(F) or C(Cl); (ii) B is defined as hydrogen,methyl, ethyl or represented by the formula (Ib)

wherein, R¹ and R² is independently hydrogen or lower alkyl; or whereinR¹ and R² together may form a 3 to 6-membered spiro ring system; and mis 0 or 1; (iii) C represents a quaternized bicyclic nitrogen containingaromatic heterocyclic ring represented by the formulae (Ic) to (Iz)

(iv) D represents CH₂, CH₂CH₂ or CH₂CO; (v) E represents a substitutedor unsubstituted benzene ring or a substituted or unsubstituted 5- or6-membered aromatic heterocyclic ring having at least one heteroatomselected from the group consisting of O, S and N, wherein theheteroaromatic ring includes is pyrrolyl, imidazolyl, pyrazolyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, isoxazolyl, oxazolyl,oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, and orthienyl; (vi) F is optionally substituted amidine or optionallysubstituted guanidine; and (vii) G is hydrogen, methyl, ethyl, C₃₋₆alkyl, C₃₋₆ cycloalkyl or a an optionally substituted 5- or 6-memberedaliphatic or a an optionally substituted 5- or 6-membered aromaticheterocyclic ring, wherein the heterocyclic ring is substituted with atleast 1-2 hetero atoms selected from the group consisting of N, O, and S(αor β α or β).
 2. A compound as recited in claim 1, where E is selectedfrom a substituted aryl or a 5- and the group consisting of anoptionally substituted benzene ring and an optionally substituted 5- or6-membered aromatic heterocyclic rings ring, comprising:


3. A compound as recited in claim 2, wherein the optional substituentsinclude on the benzene ring and the 5- or 6-membered aromaticheterocyclic rings of E are selected from the group consisting ofchloro, fluoro, cyano, hydroxy, amino, carboxy, acetyl, methoxy, ethoxy,trifluoromethyl, pyrrolidinyloxy, and piperidinyloxy.
 4. A compound asrecited in claim 1, wherein the preferred examples of “-C-D-E-F” includecomprises one of the following organic residues


5. The compound of formula (I) as recited in claim 1, which is selectedfrom the following group of compounds consisting of:


6. A method of treating a bacterial infection comprising administeringto a mammal in need thereof an antibacterially effective amount of acompound as recited in claim
 1. 7. A pharmaceutical compositioncontaining as an active ingredient, at least one compound as recited inclaim 1 and at least one pharmaceutically acceptable carrier or diluent.8. A method of treating a bacterial infection comprising administeringto a mammal in need thereof a combination of (i) an antibacteriallyeffective amount of a compound as recited in claim 1, and (ii) atherapeutically effective amount of a β-lactamase inhibitor selectedfrom the group consisting of:


9. A pharmaceutical composition containing as an active ingredient atleast (i) one compound as recited in claim 1 and (ii) a therapeuticallyeffective amount of a β-lactamase inhibitor selected from the groupconsisting of:


10. The method as recited in claim 8, wherein (i) and (ii) areadministered simultaneously, sequentially, or separated in time.
 11. Thepharmaceutical composition as recited in claim 9, wherein the ratio ofthe weight of (i) to the weight of (ii) is in the range of from about1:20 to about 20:1.
 12. A process for preparing a compound of formula(I) as recited in claim 1, the process comprising one of the followingprocesses: Process I wherein the intermediate VIII (q=0, Y=chloride) iscoupled with intermediate (IX) to provide the intermediate (X) followedby removal of protecting groups to provide the compound of formula (I)

or Process II wherein the intermediate VIII (q=1, Y=iodide) is coupledwith intermediate (IX) and subsequently reducing the sulfoxide tosulfide providing the intermediate (XI) by removal of the protectinggroups provides the compound of formula (I)

wherein in the formula VIII, P¹ is a suitable carboxy protecting group.13. A compound of formula (I) or a pharmaceutically acceptable saltthereof:

wherein in the formula (I), (i) A is defined by the formula (Ia)

(ii) B is defined as hydrogen, methyl, ethyl or represented by theformula (Ib):

wherein, R¹ and R² are independently hydrogen or lower alkyl; or whereinR¹ and R² together may form a 3 to 6 membered spiro ring system; and mis 0 or 1; and (iii) wherein “-C-D-E-F” is selected from the groupconsisting of one of the following organic residues:


14. A compound of formula (I) or a pharmaceutically acceptable saltthereof:

wherein the compound is selected from the group consisting of thefollowing compounds: